(formoterol fumarate dihydrate) 6 ug/Metered dose and 12 ug/Metered dose Dry Powder Inhalers for Oral Inhalation (Bronchodilator)
AstraZeneca Canada Inc. 1004 Middlegate Road Mississauga, Ontario
Date of Preparation: February 2, 2000
1M4 Date of Revision:
Control No. 109733 OXEZE(r) and TURBUHALER(r) are trade-marks of the AstraZeneca group of companies.
OXEZE(r) TURBUHALER(r) (formoterol fumarate dihydrate) 6 ug/Metered dose and 12 ug/Metered dose
Bronchodilator
The active ingredient in OXEZE TURBUHALER, formoterol, produces bronchodilation by stimulation of the b2 adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of smooth muscle fibres. Following inhalation from OXEZE TURBUHALER (formoterol fumarate dihydrate), a marked improvement in pulmonary function is observed within 1-3 minutes. This fast onset of action is similar to that seen with short-acting bronchodilators (e.g., terbutaline, salbutamol). Approximately 80% of peak effect is attained within 15 minutes of administration. In addition, formoterol has a mean duration of bronchodilator effect of 12 hours after a single dose, much like other long-acting b2-agonists.
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 21-37% 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 6-10% of the metered dose of formoterol is excreted unmetabolized in the urine. About 20% of an intravenous dose is excreted unchanged in the urine. The terminal half-life after inhalation is estimated to be 8 hours.
OXEZE TURBUHALER (formoterol fumarate dihydrate) is indicated for the treatment and prevention of symptoms of reversible obstructive airways disease including asthma in patients * 6 years of age and older. *This includes patients on concomitant inhaled corticosteroid therapy: requiring long-term twice daily maintenance treatment of asthma requiring occasional use of a bronchodilator experiencing acute bronchoconstriction with nocturnal asthma with exercise-induced bronchoconstriction. Corticosteroids should not be stopped because formoterol is prescribed. OXEZE TURBUHALER should not be used in patients whose asthma can be managed by only occasional use of inhaled short-acting beta2-agonists. When treating asthma patients, OXEZE TURBUHALER should be used only as additional therapy for patients whose conditions are not adequately controlled using low-to-medium dose inhaled corticosteroids or whose disease severity clearly warrants the initiation of treatment with two maintenance therapies, i.e. OXEZE TURBUHALER in addition to an inhaled corticosteroid (see WARNINGS).
OXEZE TURBUHALER (formoterol fumarate dihydrate) is contraindicated when there is known hypersensitivity to formoterol or inhaled lactose. Like other sympathomimetic amines, OXEZE TURBUHALER should not be used in patients with tachyarrhythmias.
Data from a large placebo-controlled US study (Salmeterol Multi-center Asthma Research Trial) comparing the safety of the long-acting beta2-adrenergic agonist salmeterol to that of a placebo added to the original asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. Although the trial results were specific to salmeterol, one of the conclusions derived from this study is that long-acting beta2-adrenergic agonists may increase the risk of asthma exacerbation and possibly asthma-related death. Although available data for formoterol fumarate dihydrate do not suggest increased risk, it can not be excluded that the findings with salmeterol may apply to all long-acting beta2-adrenergic agonists including formoterol fumarate dihydrate, the active ingredient in OXEZE TURBUHALER. When treating asthma patients, OXEZE TURBUHALER should be used only as additional therapy for patients whose conditions are not adequately controlled using low-to-medium dose inhaled corticosteroids or whose disease severity clearly warrants the initiation of treatment with two maintenance therapies, i.e. OXEZE TURBUHALER in addition to an inhaled corticosteroid.
Use of Anti-Inflammatory Agents
Treatment of Acute Symptoms
OXEZE TURBUHALER may be used as a regular twice daily maintenance regimen and/or as needed to treat asthma. The management of asthma should normally follow a stepwise programme, as advised in asthma management guidelines, with patient response monitored clinically and by lung function tests. When used as regular, twice daily maintenance treatment, OXEZE TURBUHALER should not be used without adequate anti-inflammatory therapy. Consideration should be given to the following in the management of asthma with OXEZE TURBUHALER: Oral or inhaled corticosteroids, or other anti-inflammatory medications 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. Increasing use of OXEZE TURBUHALER or other fast-acting bronchodilators 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.
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, OXEZE TURBUHALER, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, arrhythmias and hypertension.
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 OXEZE TURBUHALER.
As with other inhaled asthma medication, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, treatment with OXEZE TURBUHALER should be discontinued immediately and alternative therapy instituted.
The number of postmarketing adverse event reports based on more than 2.4 million patient treatment-years is low (<0.01%). The most commonly reported adverse symptoms, which constitute the majority of the reports, are listed as adverse side effects of b2-agonist therapy (see ADVERSE REACTIONS). There has been no indication of any particularly serious or unanticipated drug related reactions.
Patients who require therapy with OXEZE TURBUHALER should also receive optimal anti- inflammatory therapy with corticosteroids. Patients must be advised to continue taking their anti-inflammatory therapy after the introduction of OXEZE TURBUHALER even when symptoms decrease. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.
Fast-acting, inhaled bronchodilators (e.g., formoterol, terbutaline, salbutamol) may be used for relief of breakthrough symptoms. Asthma may deteriorate acutely over a period of hours or slowly over several days or longer. The total maximum daily dose of OXEZE TURBUHALER should not be exceeded. Should symptoms persist, or treatment with fast- 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. Patients requiring increasing doses or inhalations of fast-acting b2-agonists for relief of symptoms should be advised to consult a physician for re-evaluation. In the case of acutely or rapidly worsening dyspnea, a doctor should be consulted immediately.
OXEZE TURBUHALER should NOT be used at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs (see below).
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 OXEZE TURBUHALER when the following conditions may exist: ischemic heart disease, cardiac arrhythmias, especially third degree atrioventricular 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 may occur after administration of OXEZE TURBUHALER. OXEZE TURBUHALER contains lactose (600 ug per 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 CONTRAINDICATlONS).
Due to the reversible hyperglycemic effect of b2-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.
Pregnant Women
The safety of OXEZE TURBUHALER during pregnancy has not yet been established (see Use in Labour and Delivery).
Lactating Women
Formoterol was found to be excreted in the milk of lactating rats after oral administration. Since there is no experience in the use of OXEZE TURBUHALER 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.
Use in Labour and Delivery
There are no well-controlled human studies that have investigated the effects of formoterol on preterm labour or labour at term. Because of the potential for b-agonist interference with uterine contractility, use of b2-agonists, such as OXEZE TURBUHALER, during labour should be restricted to those patients in whom the benefits clearly outweigh the risks.
No adjustment of dose should be required in the elderly, or in patients with renal or hepatic impairment, at the recommended normal doses. (See also WARNINGS and PRECAUTIONS for patients with cardiovascular disorders).
OXEZE TURBUHALER is not currently recommended for on-demand use in children younger than 12 years of age. For long-term maintenance therapy and prevention of exercise- induced bronchoconstriction, OXEZE TURBUHALER is not recommended for children younger than 6 years of age due to limited clinical data in this age group.
In children and adolescents the severity of asthma may be variable with age and periodic reassessment should be considered to determine if continued therapy with OXEZE TURBUHALER is still indicated. Compliance, especially neglect of anti-inflammatory therapy and overuse of rescue medication , should be carefully followed in this age group.
Beta-Receptor Blocking Agents
Beta-receptor blocking agents, especially non-selective ones, may partly or totally inhibit the effect of beta-stimulants. Should a patient treated with OXEZE TURBUHALER also require concomitant treatment with a beta-blocker, it is recommended that a beta-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), monoamine oxidase 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 monoamine oxidase 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.
See illustrated INFORMATION FOR THE CONSUMER section. It is important that patients understand how to use OXEZE TURBUHALER 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:
For Long-term Twice Daily Maintenance treatment of asthma:
Adults:
The usual dose is 6 or 12 ug, twice daily, at 12 hour intervals. Some adults may need 24 ug, twice daily. In adults, the maximum recommended daily dose is 48 ug.
Children (6 -16 years)
: The usual dose is 6 or 12 ug, twice daily, at 12 hour intervals. In children, the maximum recommended daily dose is 24 ug.
For the relief of acute bronchoconstriction in patients who are on maintenance treatment with OXEZE TURBUHALER:
Adults and Adolescent Children:
The usual dose is 6 or 12 ug as needed.
For relief of acute bronchoconstriction and prevention of bronchospasm for patients who remain symptomatic on inhaled corticosteroid:
Adults and Adolescent Children:
The usual dose is 6 or 12 ug as needed.
For the prevention of exercise-induced bronchoconstriction:
Adults and Children 6 years of age and older
: 6 or 12 ug before exercise. When OXEZE TURBUHALER is used on demand, the maximum dose during a 24 hour
period should not normally exceed 72 ug in adults and 48 ug in adolescent children. Prolonged use (more that 3 consecutive days) of more than 48 ug may be a sign of sub- optimal asthma control and treatment should be reassessed. 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 fast-acting, inhaled b2-agonist;
Need for more inhalations than usual of fast-acting, inhaled b2-agonist.
OXEZE TURBUHALER 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 OXEZE TURBUHALER as maintenance treatment for asthma, even when symptoms decrease. Patients should be cautioned regarding potential adverse cardiovascular effects, such as palpitations or chest pain. In patients receiving OXEZE TURBUHALER other inhaled medications should be used only as directed by the physician. Parents/guardians of children or adolescents who have been prescribed OXEZE TURBUHALER should be alerted to the general concern regarding asthma therapy compliance, especially neglect of anti-inflammatory therapy and overuse of fast- acting b2-agonists.
OXEZE TURBUHALER has been used by more than 29,000 patients in clinical trials. The total post marketing exposure to OXEZE TURBUHALER is more than 2.4 million treatment- years. The frequencies listed below are from the combined clinical trial and post marketing experience. 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 >= 1% and <10%): tremor, palpitations and headache; uncommon:muscle cramps, tachycardia, agitation, restlessness and sleep disturbances; rare:cardiac arrythmias (e.g., atrial fibrillation, supraventricular tachycardia, extrasystoles), hypersensitivity reaction (e.g., bronchospasm, exanthema, urticaria, pruritus), hypokalemia; very rare:(frequency < 0.01%) angina pectoris, hyperglycemia, taste disturbance, dizziness, and variations in blood pressure. The incidence of adverse events, irrespective of causality towards the drug, from four controlled trials (duration 1, 3, 3 and 6 months, respectively) with OXEZE TURBUHALER is presented in the following table.
Table 1 Incidence Of Adverse Events (Irrespective Of Causality) With Frequency Higher Than Placebo In Four Controlled Trials Of Duration 1, 3, 3 And 6 Months Respectively.
| OXEZE TURBUHALER | Placebo TURBUHALER | |||
| Total | 6 ug b.i.d. | 12 ug b.i.d. | ||
| No. (%) | No. (%) | No. (%) | No. (%) | |
| Total Number of Evaluable Patients | 359 | 190 | 169 | 412 |
| Headache | 66 (18%) | 15 (8%) | 51 (30%) | 84 (20%) |
| Tremor | 11 (3%) | 4 (2%) | 7 (4%) | 2 (0%) |
| Pharynx Disorder | 18 (5%) | 3 (2%) | 15 (9%) | 10 (2%) |
| Cramps | 10 (3%) | 3 (2%) | 7 (4%) | 3 ( 1%) |
There is limited clinical experience on the management of overdose. An overdose would likely lead to effects that are typical of b2-adrenergic agonists: tremor, headache, palpitations. Metabolic acidosis and hypertension may also occur. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic treatment may be indicated.
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 corticosteroid dosage which should be administered under medical supervision. Since there may be serious adverse effects associated with excessive dosing, the dosage should not be increased beyond the maximum recommended dose. Dosage should be individualized and patient response should be monitored by the prescribing physician on an ongoing basis.
As a twice daily regular treatment, OXEZE TURBUHALER 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. The dose of OXEZE TURBUHALER 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 ug from OXEZE TURBUHALER, twice daily, at 12 hour intervals. Some patients may need 24 ug twice daily. In adults, the maximum recommended daily dose is 48 ug.
Children (6-16 years)
: The usual dose is 6 or 12 ug, twice daily, at 12 hour intervals. In children, the maximum recommended daily dose is 24 ug.
Adults and Adolescent Children (12-16 years)
: The usual dose is 6 or 12 ug as needed.
Adults and Adolescent Children (12-16 years)
: The usual dose is 6 or 12 ug as needed.
Adults and Children 6 years of age and older
: 6 or 12 ug before exercise. When OXEZE TURBUHALER is used on demand, the maximum dose during a 24 hour
period should not normally exceed 72 ug in adults and 48 ug in adolescent children. Prolonged use (more than 3 consecutive days) of more than 48 ug may be a sign of sub- optimal asthma control and treatment should be reassessed. In children and adolescents, 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 OXEZE TURBUHALER is still indicated (see PRECAUTIONS). OXEZE TURBUHALER is available in two strengths, 6 or 12 ug per inhalation. Use of the higher strength is recommended for patients requiring 12 ug or more, twice daily. OXEZE TURBUHALER is not currently recommended for on-demand use in children younger than 12 years of age. For long-term maintenance therapy and prevention of exercise-induced bronchoconstriction, OXEZE TURBUHALER is not recommended for children younger than 6 years of age due to 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.
Proper Name: formoterol fumarate dihydrate Chemical Structure:
Molecular Formula: C42H56N4O14 Molecular Weight: 840.9
Chemical Name
: (R *,R *)-(+-)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1- methylethyl]amino]ethyl]phenyl] formamide, (E)-2-butendioate(2:1), dihydrate
Description
: Formoterol fumarate dihydrate is a white to off-white or slightly yellow non- hygroscopic crystalline powder.
Dissociation Constant
: The pKa of formoterol fumarate dihydrate at 25degC is 7.9 for the phenolic group and 9.2 for the amino group.
Partition Coefficient
: The octanol-water partition coefficient at 25degC is 2.6.
Active
: formoterol fumarate dihydrate 6 or 12 ug/inhalation.
Non-Medicinal
: Lactose monohydrate.
OXEZE TURBUHALER should be stored at room temperature between 15degC and 30degC with the cover tightened, away from moisture.
OXEZE TURBUHALER (formoterol fumarate dihydrate) is supplied in two strengths: 6 ug/metered dose (60 doses) and 12 ug/metered dose (60 doses). The strength of OXEZE TURBUHALER can be identified by the colour of the turning grip: the 6 ug/metered dose strength has a light greenish-blue turning grip, and the 12 ug/metered dose strength has a dark greenish-blue turning grip. OXEZE TURBUHALER also contains lactose (600 ug per metered dose). This amount does not normally cause problems in lactose-intolerant people. OXEZE TURBUHALER cannot be refilled and should be discarded when empty.
OXEZE(r) TURBUHALER(r) (formoterol fumarate dihydrate) Before using OXEZE TURBUHALER, read this leaflet carefully. It contains general points about OXEZE TURBUHALER and should add to more specific advice from your doctor or pharmacist. Please keep this leaflet to refer to until you have used up all medication in OXEZE TURBUHALER.
Your doctor has prescribed OXEZE TURBUHALER because your asthma is not well controlled with your current asthma medications (i.e. inhaled glucocorticosteroids along with an as needed short-acting bronchodilator medication). An inhaled glucocorticosteroid must always be used when taking OXEZE TURBUHALER. OXEZE TURBUHALER contains an inhalation powder. The powder is a mixture of the medicine formoterol and lactose. (It is unlikely that the very small amount of lactose in the powder would cause any problems to patients who are intolerant to lactose.) Formoterol is a fast-acting bronchodilator with a long duration of action. It widens the airways enabling you to breathe more easily. You usually notice an effect from OXEZE TURBUHALER within 1-3 minutes. TURBUHALER is the brand name for a multiple dose, dry powder inhaler. When you breathe in through the mouthpiece, your breath provides the necessary force to deliver the drug to your lungs. Twice daily maintenance treatment with OXEZE TURBUHALER gives 24 hour relief or prevention of symptoms such as shortness of breath in patients with asthma and other similar conditions.
Tell your doctor: about all health problems you have now or have had in the past, especially if you have a heart disorder, diabetes, or a disturbed thyroid function (thyrotoxicosis). about all medicines you take, including those you have bought without a prescription. Certain types of medicines for example beta-blockers (some heart medicines or eye drops) may reduce or block the effect of OXEZE TURBUHALER when taken at the same time. if you have ever had a bad, unusual or allergic reaction to formoterol or lactose or to other medicines for breathing problems. if you are pregnant, plan to become pregnant or are breast feeding.
Before you start using OXEZE TURBUHALER for the first time it is important that you read the instructions below and follow them carefully. TURBUHALER is a multidose inhaler from which very small amounts of powder are administered. When you breathe in through TURBUHALER the powder is delivered to the lungs. It is therefore important that you inhale forcefully and deeply through the mouthpiece. OXEZE TURBUHALER is very easy to use.
To administer a dose, simply follow the instructions below. Fig. 1 Fig. 2 Unscrew and lift off the cover.
with the grip downwards (Fig. 1). To load the inhaler with a dose
.
CLIC
K
The "click" you heard means the inhaler is ready to use.
. Do
breathe out through the mouthpiece.
Place the mouthpiece gently between your teeth, close your lips and breathe in forcefully and deeply through your mouth (Fig. 2). Do not chew or bite on the mouthpiece.
If more than one dose has been prescribed, repeat the above steps. Replace the cover. If you accidentally drop, shake or breathe out into OXEZE TURBUHALER after it is loaded, you will lose your dose. If this happens, you should load a new dose and inhale it.
As the amount of powder dispensed is very small, you may not be able to taste it after inhalation. However, you can still be confident that the dose has been inhaled if you have followed the instructions.
Clean the outside of the mouthpiece once a week with a
tissue.
use water or any other fluid. If fluid enters the inhaler it may not work properly.
Approx. 20 doses left EMPTY OXEZE TURBUHALER has a dose indicator. A new TURBUHALER provides 60 doses for inhalation. When a red mark first appears in the little window underneath the mouthpiece, there are approximately 20 doses left. Now is the time to obtain your next inhaler. When the red mark reaches the bottom of the window, you should discard your inhaler. The sound you hear when you shake the inhaler is produced by a drying agent, not medication. OXEZE TURBUHALER cannot be re-filled with drug and should be discarded.
Follow your doctor's instructions carefully. They may differ from the information contained in this leaflet.
For Long-term Twice Daily Maintenance treatment of asthma:
Adults:
The usual dose is 6 or 12 ug, twice daily, at 12 hour intervals. Some adults may need 24 ug, twice daily. In adults, the maximum recommended daily dose is 48 ug.
Children (6-16 years)
: The usual dose is 6 or 12 ug, twice daily, at 12 hour intervals. In children, the maximum recommended daily dose is 24 ug.
For the relief of acute bronchoconstriction (asthma attacks) in patients who are on maintenance treatment with OXEZE TURBUHALER:
Adults and Adolescent Children (12-16 years):
The usual dose is 6 or 12 ug as needed.
For relief of acute bronchoconstriction (asthma attacks) and prevention of bronchospasm (shortness of breath or chest tightness) for patients who remain symptomatic on inhaled corticosteroids:
Adults and Adolescent Children (12-16 years):
The usual dose is 6 or 12 ug as needed. Treatment should always aim for the lowest effective dose.
For the prevention of exercise-induced asthma:
Adults and Children 6 years of age and older
: 6 or 12 ug before exercise. When OXEZE TURBUHALER is used on demand, the maximum dose during a 24 hour
period should not normally exceed 72 ug in adults and 48 ug in adolescent children. You usually get an effect from OXEZE TURBUHALER within 1-3 minutes. The effect of OXEZE TURBUHALER lasts up to 12 hours. OXEZE TURBUHALER is not currently recommended for on-demand use in children younger than 12 years of age. For long-term maintenance therapy and prevention of exercise- induced asthma, OXEZE TURBUHALER is not recommended for children younger than 6 years. You should see your doctor if: your usual dose does not provide relief the effects of one dose last less than 12 hours you use more than 48 ug of OXEZE TURBUHALER on 3 days in a row. These may be signs that your asthma is getting worse.
.
If you miss a dose of your twice daily maintenance treatment of OXEZE TURBUHALER and remember within 6 hours, you should take your usual dose as soon as possible. Then go back to your regular schedule. If it is more than 6 hours when you remember, do not take the missed dose. Just take the next dose on time.
. If you are still unsure, check with your doctor or pharmacist to see what you should do.
There is no clinical experience on the management of overdose. The most common signs and symptoms that may occur after overdosage are trembling, headache and rapid heartbeat. Contact your doctor or go to the nearest hospital immediately if any of these symptoms bother you, or if you think you have taken too much OXEZE TURBUHALER.
Usually you do not feel any side effects when you use OXEZE TURBUHALER. However, like any medication, OXEZE TURBUHALER may cause side effects in some people. The most common side effects are trembling, rapid heartbeat, and headache. Rare or uncommon side effects are irregular heartbeat, muscle cramps, skin rash, agitation, chest pain, restlessness and sleep disturbances and in extreme cases, drugs for inhalation may cause bronchospasm (shortness of breath, chest tightness). Side effects that do occur are usually mild and disappear by themselves within one or two weeks of treatment, however, be sure to tell your doctor if any of the side effects bother you or if they continue. Also contact your doctor if any other unusual effects bother you while you are using OXEZE TURBUHALER.
A large US clinical trial showed an increased risk of asthma related death and serious respiratory-related outcomes in patients who used salmeterol (a long-acting bronchodilator) in addition to their usual asthma therapy, in comparison with those who used placebo in addition to their usual asthma therapy. The active ingredient in OXEZE is formoterol fumarate dihydrate, which is a different long-acting bronchodilator. Although similar findings have not been seen with formoterol fumarate dihydrate, the risks associated with salmeterol may also apply to other long- acting bronchodilator drugs including OXEZE. Your doctor has prescribed OXEZE TURBUHALER because your asthma is not well controlled with your current asthma medications (i.e. inhaled glucocorticosteroids along with an as needed short-acting bronchodilator medication). An inhaled glucocorticosteroid must always be used when taking OXEZE TURBUHALER.
Use of OXEZE TURBUHALER will not affect your ability to drive or to operate any tools or machines.
Remember to keep OXEZE TURBUHALER out of the reach of children. Always replace the cover after using OXEZE TURBUHALER. Store the inhaler at room temperature (15-30degC) away from moisture.
You must continue to regularly take the anti-inflammatory medications your doctor has prescribed. Your anti-inflammatory medications and OXEZE TURBUHALER are designed to act together to best treat your condition. Even though you feel better, DO NOT STOP or reduce your doses of anti-inflammatory medications or OXEZE TURBUHALER without first consulting your doctor.
You may be prescribed the following AstraZeneca medications to help control your asthma. It is important that you understand how to tell them apart and when to use each medication.
| Medication | Strength | Identification |
| OXEZE TURBUHALER (formoterol) | 6 ug/dose | Turning grip is light greenish-blue. A braille code is embossed on the turning grip. |
| OXEZE TURBUHALER (formoterol) | 12 ug/dose | Turning grip is dark greenish-blue. A braille code is embossed on the turning grip. |
| PULMICORT TURBUHALER (budesonide) | 100 ug/dose | Turning grip is light brown. Budesonide 100 is embossed on the turning grip. |
| PULMICORT TURBUHALER (budesonide) | 200 ug/dose | Turning grip is brown. Budesonide 200 is embossed on the turning grip. |
| PULMICORT TURBUHALER (budesonide) | 400 ug/dose | Turning grip is dark brown. Budesonide 400 is embossed on the turning grip. |
| BRICANYL TURBUHALER (terbutaline) | 0.5 mg/dose | Turning grip is blue. Terbutaline sulfate 0.5 mg/dose is embossed on the turning grip. |
Specific information on product identification is provided on the drug product label. Ask your doctor or pharmacist for clarification if you are having difficulty understanding when or how often your medications should be taken.
If the relief of your asthma is not as good as usual or does not last as long as usual (12 hours), TELL YOUR DOCTOR RIGHT AWAY. A change from "usual" includes more wheezing, coughing, tightness or shortness of breath. If you are using more of your fast-acting bronchodilator medication or if you feel that it is less effective TELL YOUR DOCTOR RIGHT AWAY. Your doctor may adjust your treatment. If your symptoms are waking you up at night, TELL YOUR DOCTOR RIGHT AWAY. Your doctor may adjust your treatment. If you have taken all your medication as instructed by your doctor and your symptoms are not relieved or you notice a sudden worsening of your shortness of breath, YOU MAY NEED EMERGENCY TREATMENT.
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AstraZeneca 2000, 2006 AstraZeneca Canada Inc.
Mississauga, Ontario
L4Y 1M4 Last revised:
Absorption and Bioavailability
Inhaled formoterol reaches the systemic circulation via two routes, absorption in the lungs (pulmonary bioavailability) and absorption in the gut (oral bioavailability). Inhaled formoterol is rapidly absorbed and the peak plasma concentration is reached about 15 minutes after inhalation. The mean pulmonary bioavailability has been estimated in two studies to be 21% and 37% of the metered dose. The total systemic availability after inhalation is approximately 46% of the metered dose.
Distribution and Metabolism
Plasma protein binding is approximately 50%. Formoterol is metabolized via direct glucuronidation and O-demethylation. Direct conjugation of formoterol, and phase 1 biotransformation followed by conjugation, are likely metabolic fates of formoterol. The oxidative metabolism is likely to be slower in cirrhotic patients, but, conjugation capacity should essentially be maintained since glucuronidation appears to be little affected in conjunction with cirrhosis. Thus, cirrhosis should not a priori be expected to reduce the capacity to eliminate formoterol. If, however, metabolic clearance really were reduced, the increase in plasma concentrations after inhalation should not hinder the use of clinically recommended doses of OXEZE TURBUHALER (formoterol fumarate dihydrate) (6-12 ug b.i.d.) even with a 50% reduction in total clearance.
Elimination
The major part of the dose of formoterol is eliminated via metabolism. After inhalation 6-10% of the metered dose of formoterol is excreted unmetabolized in the urine. Following i.v. infusion of formoterol, about 19% of the dose was excreted in urine as unmetabolized formoterol within 24-48 hours. Less than 10% of the nominal dose was recovered intact after inhalation without concomitant charcoal. A considerable fraction of the dose might be excreted in urine as metabolite(s) of formoterol (e.g., Met1), or as conjugates of these metabolite(s). The terminal half-life after inhalation is estimated to be around 8 hours.
A dose-response relationship was evident when single doses of OXEZE TURBUHALER were investigated within the dose range of 3 to 48 ug. Compared with placebo, all tested doses resulted in statistically significant increases in mean FEV1 values, however, the maximum increase after 3 ug was not significantly different from placebo. As the maximum effect on FEV1 and the duration of efficacy are important measures of clinical efficacy, the 3 ug dose was considered a clinically less appropriate dose, especially as the tolerability of the higher doses was good. The 6 ug dose was thus defined as the lowest effective dose. OXEZE TURBUHALER has an onset of action (1 to 3 minutes) similar to that seen with short-acting inhaled b2-agonists and faster than that with salmeterol. Single doses of 6, 12, 24 and 48 ug OXEZE TURBUHALER result in l2-hour duration of bronchodilation. The duration is dose- dependent and the duration for 12 ug OXEZE TURBUHALER is similar to that of 50 ug salmeterol. A dose-dependent tremor of mild or moderate intensity was observed in healthy subjects not earlier exposed to OXEZE TURBUHALER. OXEZE TURBUHALER in doses up to and including 48 ug did not statistically significantly increase the pulse rate, neither in healthy subjects nor in asthmatics as compared with placebo. A clinically relevant increase in pulse rate was observed in healthy subjects after a cumulative dose of 72 ug of OXEZE TURBUHALER. When a cumulative dose of 72 ug OXEZE TURBUHALER was given to healthy subjects, statistically significant but clinically not important increases in systolic and decreases diastolic blood pressure were found. No important changes were found when blood pressure was monitored in patients with asthma receiving single doses or repeated daily doses of 48 ug of OXEZE TURBUHALER. An expected dose-response relationship has been documented for the prolongation of the QTc time, with a single dose of 24 ug in healthy subjects being significantly different from placebo. However, the absolute changes seen even after cumulative dose of 72 ug OXEZE TURBUHALER in healthy subjects cannot be considered clinically important. It should be noted that the QTc time may not be the best measure of cardiac effects. The QTc time may even be misleading when QT intervals and heart rate change at the same time. An initial decrease in S-K+ was noted in healthy subjects after administration of OXEZE TURBUHALER but a rapid tolerance to the hypokalemic effect was noted. No clinically significant decreases in S-K+ were reported in studies in patients with asthma. No hypokalemic tendency was noted in the OXEZE TURBUHALER long-term studies. A high cumulative dose of OXEZE TURBUHALER was associated with statistically significant, but clinically not important increases in plasma glucose and lactate in healthy subjects.
The acute toxicity of formoterol was studied in mice and rats after inhalation and oral administration. The inhalation LD50 values in mice and rats were estimated to be >280 mg/kg and 40-200 mg/kg respectively. The oral LD50 values were estimated to be in the range of >2000 mg/kg in adult mice and rats, and 500-1000 mg/kg in young rats (12-14 days old). Symptoms of acute toxicity were decreased motor activity, abdominal respiration, tremor, increased salivation and chromodacryorrhea. Myocardial lesions were found in some severely affected animals. This is an expected finding with a high dose of b-adrenoceptor stimulating agents such as isoprenaline, salbutamol and terbutaline. The effects noted in the single dose studies are those which can be expected with a potent b- agonist.
The general toxicity after repeated administration of formoterol was studied in mice, rats and dogs after inhalation and oral administration. Studies in young rats were also performed.
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/Man) | Results and Observations | |
| C max | AUC | ||||
| Mouse | p.o. | 0.1 | <2.2 | n.c. | - slight increase in serum urea (dose-dependent) |
| 3 months | 1.0 | 37 | 25 | - minor decrease in adrenal weights (medium - high dose) | |
| 10.0 | >343 | 214 | - increased respiratory frequency, decreased motor activity, increased salivation and | ||
| signs of cyanosis (gradually appearing in high dose; most pronounced in males) | |||||
| - increase in body weight (high dose females) | |||||
| - slight decrease in serum phosphate (high dose) | |||||
| - slight increase in serum ALT activity (high dose) | |||||
| - minor increase in spleen and liver weights (high dose females) | |||||
| Rat | inhal | 0.12 | - | - | - increase in body weight gain |
| 5 days | 0.80 | - | - | - increase in heart weight (females) | |
| 3.7 | - | - | - solitary histopathological microfocal leukocyte foci in the heart (2 high dose males of | ||
| 6) | |||||
| inhal | 0.082 | 60 | 63 | - tachycardia | |
| 3 months | 0.26 | 163 | 108 | - slight increase in PCV, Hb and number of RBC (females) | |
| 0.87 | 341 | 215 | - reduction in platelet count (dose-dependent in males) | ||
| - decrease in blood glucose (dose-dependent) | |||||
| - increase in heart weight (more pronounced in females) | |||||
| - increase in PCV (medium - high dose males) | |||||
| - slight increase in serum urea (medium - high dose) | |||||
| - increase in serum ALT activity (medium - high dose males) | |||||
| - increased body weight gain (high dose females) | |||||
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/Man) | Results and Observations | |
| C max | AUC | ||||
| inhal | 0.026 | 16 | 18 | - tachycardia | |
| 6 months | 0.13 | 63 | 68 | - slight increase in Hb, hematocrit and/or number of RBC (females) | |
| 0.85 | 278 | 264 | - slight reduction in platelet count | ||
| - increase in serum urea (dose-dependent in males) | |||||
| - decrease in blood glucose (possibly dose dependent in females) | |||||
| - small increase in serum ALT activity | |||||
| - slight increase in serum potassium (more pronounced in females) | |||||
| - increase in urine volume | |||||
| - slight decrease in urine osmolality (low - medium dose females) | |||||
| - slight increase in urinary pH | |||||
| - increase in heart weight | |||||
| - minimal histopathological reactive changes in lungs and nasal cavity | |||||
| - increased food consumption (medium - high dose) | |||||
| - slight decrease in thymus weight (medium - high dose) | |||||
| - minimal histopathological foci of myocardial fibrosis (medium - high dose) | |||||
| - increase in body weight gain ( high dose females) | |||||
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/Man) | Results and Observations | |
| C max | AUC | ||||
| Young | p.o. | 0.2 | >=3.3 | n.c. | - slight increase in total leukocyte count |
| rat | 3 months | 0.8 | 8.1 | 17 | - slight increase in serum urea (dose-dependent in females) |
| original | 3 | 29 | 60 | - decrease in blood-glucose (dose-dependent in females) | |
| study | - increase in serum potassium | ||||
| - testicular atrophy (not dose-dependent; also found in control animals) | |||||
| - increase in heart weight (medium - high dose males) | |||||
| - minimal histopathological foci of myocardial changes (medium dose males; high dose | |||||
| both sexes) | |||||
| - slight increase in serum ALT activity (high dose males) | |||||
| - decrease in testis weight (high dose) | |||||
| Young | p.o. | 0.03 | - | - | - testicular findings in original study not reproducible |
| rat cont. | 3 months | 0.2 | - | - | - decreased water consumption |
| repeat | 0.8 | 9.8 | 15 | - increased incidence of hyperemic scrotum and distinctly visible testes (also with | |
| study in males | 3 | 37 | 56 | salbutamol) - increase in body temperature | |
| - increase in lung and spleen weights (medium - high dose) | |||||
| - increased food consumption (high dose) | |||||
| - increase in heart weight (high dose) | |||||
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/Man) | Results and Observations | |
| C max | AUC | ||||
| inhal | 0.028 | 18 | 15 | - tachycardia | |
| 3 months | 0.16 | 97 | 82 | - increase in total leukocyte count | |
| 0.78 | 380 | 291 | - slight decrease in blood glucose (females) | ||
| - increase in body weight gain (medium - high dose males) | |||||
| - increase in food consumption (medium - high dose males) | |||||
| - slight increase in the number of RBC (medium - high dose females) | |||||
| - increase in heart weight (medium - high dose) | |||||
| - slight increase in Hb (high dose females) | |||||
| Dog | inhal | 0.0005 | 1.7 | n.c. | - hyperemia of the mucosa and abdominal skin |
| 5 days | 0.0029 | 6.3 | 5.3 | - tachycardia | |
| 0.015 | 48 | 44 | - slight non-dose-dependent decrease in Hb, hematocrit and number of RBC | ||
| - chronic bronchopneumonia (males; not caused by but possibly exacerbated by | |||||
| treatment) | |||||
| - hyperventilation and cough (high dose males) | |||||
| - slight to moderate foci of myocardionecrosis/fibrosis (high dose) | |||||
| inhal | 0.0005 | 1.8 | n.c. | - slight body weight increase (dose-dependent) | |
| 1 month | 0.0029 | 6.2 | 6.4 | - tachycardia related to drug administration | |
| 0.015 | 51 | 44 | - slight (low - medium dose) to moderate (high dose) histopathological foci of | ||
| myocardial fibrosis | |||||
| - hyperemia of the mucosa and abdominal skin (dose-dependent) | |||||
| - slight decrease in Hb, hematocrit and number of RBC (medium - high dose) | |||||
| - ventricular arrhythmias in some individuals (1 of 6 medium dose and 3 of 6 high dose | |||||
| males) | |||||
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/Man) | Results and Observations | |
| C max | AUC | ||||
| p.o. | 0.002 | 3.9 | n.c. | - tachycardia | |
| 1 month | 0.015 | 25 | 29 | - hyperemia of the mucosa and abdominal skin | |
| 0.1 | 98 | 217 | - slight non-dose-dependent increase in serum urea and creatinine | ||
| - bilateral periorbital edema (medium - high dose) | |||||
| - occasional ventricular arrhythmia (1 medium dose animal of 6 and 3 high dose | |||||
| animals of 6) | |||||
| - slight decrease in urinary pH | |||||
| - occasional laboured respiration (high dose) | |||||
| - slight decrease in heart, spleen, kidneys, testes, prostate and epididymis weights (high | |||||
| dose males) | |||||
| - treatment-related moderate foci of myocardial fibrosis (4 high dose animals of 6) | |||||
| p.o. | 0.0007 | 1.4 | n.c. | - hyperemia of the mucosa and abdominal skin (dose-dependent) | |
| 12 months | 0.0086 | 17 | 24 | - transient discoloration of the claw keratin (dose-related) | |
| 0.092 | 131 | 265 | - tachycardia | ||
| - slight non-dose-dependent increase in serum urea and creatinine | |||||
| - papillary myocardial fibrosis (dose-dependent; 2 low, 3 medium and 5 high dose | |||||
| animals of 10) | |||||
| - ventricular ectopic extrasystole (1 medium dose female, 3 high dose females and 4 | |||||
| high dose males of 5) | |||||
| - slight decrease in Hb and hematocrit (medium - high dose) | |||||
| - slight increase in serum potassium (high dose) | |||||
| - slight increase in blood glucose (high dose males) | |||||
| - slight increase in serum ALT activity (high dose females) | |||||
n.c. = not calculable * Based on a human dose of 24 ug.
The effects observed in the repeat dose toxicity studies in mice, rats and dogs are those which can be expected with a potent b2-agonist. The most prominent are those on the cardiovascular system with tachycardia, ventricular arrhythmia and myocardial lesions at high doses. In some studies slightly elevated serum potassium was noted, which is contrary to what is usually seen clinically, i.e., reduced serum potassium after acute exposure to a b2-agonist. In this context it should be mentioned that blood sampling for clinical chemistry in toxicological studies is routinely performed about 24 hours after dosing. Thus, the slightly elevated serum potassium may be due to a rebound effect. The same explanation may also be valid for other discrepancies between clinical and toxicity studies, e.g., blood glucose variations. A slight elevation of ALT activity was noted in some of the studies which may indicate effects on the liver although no morphological changes were found. The findings of an increased incidence of testicular atrophy noted in the original study in young rats with formoterol was not reproducible. All other repeat dose studies performed with formoterol in mice, rats and dogs (adult animals) have been reviewed with regard to testicular atrophy. There is no evidence from these studies that formoterol causes testicular atrophy. It is concluded that the testicular effects noted in the first study in young rats are equivocal in nature and are therefore considered to be of no relevance in the clinical setting.
The mutagenic potential of formoterol was studied in the Ames test, Mouse Lymphoma L5178 TK +/- assay, in vitro chromosome aberration test in human lymphocytes and the rat micronucleus test. In the Ames test two batches of formoterol were each tested in two independent experiments. A weak but significant increase in the number of revertant colonies was seen in one of the experiments using each batch. However, since the mutagenic effects were neither reproducible nor dose related, it was concluded that formoterol was not mutagenic in this test. Neither was it mutagenic at the thymidine kinase locus in L5178Y mouse lymphoma cells, nor did it not induce chromosome aberrations in human lymphocytes in vitro or micronuclei in rats treated with formoterol by inhalation. Considering that the mouse lymphoma and chromosome aberration tests are generally more sensitive than the Ames test, and the low and inconsistent activity seen in the two different Ames tests, it was concluded that formoterol is not an in vitro mutagen. The negative results in the micro- nucleus test indicated that the compound is not mutagenic in vivo either.
The carcinogenic potential of formoterol was studied in mice after oral administration and in rats after inhalation. The only treatment related findings were increased incidence of uterine leiomyomas in mice and one mesovarian leiomyoma in rats. These are expected findings in rodents with b-stimulating agents.
| Species | Route Duration | Dose mg/kg | Exposure Ratio (Animal/man) | Results and Observations | |
| C max | AUC | ||||
| Mouse | p.o. | 0.1 | 5.6 | n.c. | -dose-related increased incidence of uterine leiomyomas |
| 24 months | 0.5 | 8.9 | 6.4 | -dose-related increased incidence of uterine leiomyomas | |
| 2.5 | 59 | 56 | -dose-related increased incidence of uterine leiomyomas | ||
| Rat | inhal | 0.005 | 4.8 | n.c. | |
| 24 months | 0.022 | 17 | 15 | ||
| 0.13 | 67 | 66 | -single mesovarian leiomyoma found, considered to be dose-related | ||
n.c. = not calculable * Based on a human dose of 24 ug.
A complete program of reproduction toxicology studies was performed in rats and rabbits. In these studies formoterol was administered either orally or by inhalation. In the fertility study in rats with formoterol given orally by gavage, a reduction in male fertility (fertility 78% of control) was noted at the high dose level (15 mg/kg) in the main study. This effect was not seen at the mid (3 mg/kg) or low (0.2 mg/kg) dose levels. This reduction in fertility was associated with a slight decrease in testes weight at the high dose level, although not statistically significant. Histological examination of the testes did not reveal an increased incidence or severity of testicular atrophy at the high dose level or any other dose level in comparison with the control group. The overall incidence of testicular atrophy in this study was within the historical control data of this laboratory. That male, but not female fertility was affected was indicated by the finding that formoterol treated satellite group females, who were mated with untreated males, showed a 100% pregnancy rate, even in the 15 mg/kg dose group. It was noted that untreated females mated with males from the 15 mg/kg dose group (male's second mate) showed reduced fertility (81% of control). At the high dose level, 15 mg/kg, the systemic exposure (Cmax and AUC) was about 1300 times the recommended human exposure. Effects upon pregnancy were studied in rats after inhalation of formoterol (dose range 0.004- 1.2 mg/kg). The maternal body weight was dose-dependently increased versus the control from the beginning of the dosing period. Dose related tachycardia was also noted. Mean placental weights were statistically significantly increased in all dose groups compared with the control group. No adverse effects which could be related to the treatment with formoterol on organogenesis or fetal development were noted up to and including 1.2 mg/kg (high dose level). Effects upon pregnancy were also studied in rabbits after oral gavage at doses of 0.2, 3.5 and 60 mg/kg. Increased maternal weight gain was observed at all dose levels, most notably at 60 mg/kg. A slight increase in placental weight and a higher proportion of fetuses with subcapsular liver cysts were also noted at 60 mg/kg. The percentage of fetuses with extra ribs and reduced and/or asymmetric/bipartite sternebrae at this dose level was also higher although considered to be of uncertain treatment relationship. There was no clear adverse effect of treatment on embryonal development at 0.2 or 3.5 mg/kg. At the high dose level systemic exposure (Cmax and AUC) was about 7000-11000 times the recommended human exposure. As to possible effects on late pregnancy, delivery and offspring development rats were treated orally by gavage with formoterol in the dose range 0.2-3.4 mg/kg. A dose-dependent increase in maternal body weight gain was noted. The number of non-pregnant females and females with total litter loss was slightly higher in the mid (0.8 mg/kg) and the high dosed groups (3.4 mg/kg). The litter weights and the mean pup weights were slightly reduced in the dose groups, but with no obvious dose dependency. There were no differences in the developmental milestones, the reflex development or the functional tests. No differences in sexual function or fertility between groups were seen (F1 generation). No serious adverse effects on reproduction were noted. The most important finding is a reduced fertility at the high dose level (about 1300 times higher than maximal recommended human systemic exposure) in the rat. Thus, it is considered that it does not represent a clinical problem.
Anderson GP. Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective b2-adrenoceptor agonist bronchodilator. Life Sci 1993; 52:2145-2160. Decker N, Quennedey MC, Rouot B, Schwartz J, Velly J. Effects of N-aralkyl substitution of b-agonists on a- and b-adrenoceptor subtypes: Pharmacological studies and binding assays. J Pharm Pharmacol 1982; 34:107-112. Derom EY, Pauwels RA. Time course of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic. Thorax 1992; 47:30-33. Faulds D, Hollingshead LM, Goa KL. Formoterol. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 1991; 42:115-137. Gronnerod TA, von Berg A, Schwabe G, Soliman S. Formoterol via Turbuhaler(r) gave better protection than terbutaline against repeated exercise challenge for up to 12 hours in children and adolescents. Respiratory Medicine 2000: 94 (7):661-667 Ind P, Borszormenyi Nagy G, Pietinalho A, Shiner R, Villasante C, Brander R, Larsson P. Formoterol 4.5 ug, used as needed via Turbuhaler(r) was as safe and well tolerated as terbutaline 0.5 mg. Eur Resp J 1999; ERS-99 (P1086). Lofdahl C-G, Svedmyr N. Formoterol fumarate, a new b2-adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy 1989; 44:264-271. Mak JCW, Grandordy B, Barnes PJ. High affinity [3H]formoterol binding sites in lung: characterization and autoradiographic mapping. Eur J Pharmacol 1994; 269:35-41. National Institute of Health, Global Strategy for Asthma Management and Prevention, NHLBI/WHO Workshop Report, March 1993, Publication #95-3659, January 1995. Nelson HS, Weiss, ST, Bleeckeer ER, Yancey SW, Dorinsky PM, and SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. CHEST, 2006; 129:15-26 Pauwels RA, Lofdahl C-G, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on asthma exacerbations. N Engl J Med, 1997; 337:1405-11. Politiek MJ, Boorsma M, Aalbers R. Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J 1999; 13:988-992. Ramsdale EH, Otis J, Kline PA, Gontovnick LS, Hargreave FE, O'Byrne PM. Prolonged protection against methacholine-induced bronchoconstriction by the inhaled b2- agonist formoterol. Am Rev Respir Dis 1991; 143:998-1001. Rott Z, Bocskei C, Poczi M, Juhasz, Larsson P, Rosenborg J. On the relative therapeutic index between formoterol Turbuhaler(r) and salbutamol pressurized metered dose (pMDI) inhaler in asthmatic patients. Eur Respir J 1998; 12(Suppl 28):324s. Sasaki H, Kamimura H, Enjoji Y, Shiobara Y. Absorption and distribution of formoterol fumarate in rats. Oyo Yakuri 1983; 25(6):981-991. Scheurs AJM et al. A dose-response study with formoterol Turbuhaler as maintenance therapy in asthmatic patients. ERJ 1996; 9:1678-1683. Seberova E and A Andersson. Oxis(r) (formoterol given by Turbuhaler(r)) showed as rapid an onset of action as salbutamol given by pMDI. Respiratory Medicine 2000, 94, 607-611. Tattersfield A, Lofdahl CG, Postma DS, Ekstrom T, Eivindson A, Schreurs A, Rasidakis A, Karlsson K, Larsson P. On demand treatment: Comparison of formoterol and terbutaline in moderate asthma. Am J Respir Crit Care Med 1999; 159 (No. 3 Pt 2):A636. The 1999 Canadian Asthma Consensus Report. Canadian Medical Association Journal, November 30, 1999; 161 (11 Suppl). Totterman KJ, Huhti L, Sutinen E, Backman R, Pietinalho A, Falck M, Larsson P, Selroos O. Tolerability to high doses of formoterol and terbutaline via Turbuhaler(r) for 3 days in stable asthmatic patients. Eur Respir J 1998; 12:573-579. Trofast J, Osterberg K, Kallstrom B-L, Waldeck B. Steric aspects of agonism and antagonism at b-adrenoceptors: Synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers. Chirality 1991; 3:443-450. van der Molen T, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. Thorax 1996; 52:535-539. Vilsvik J, Ankerst J, Palmqvist M, Persson G, Schaanning J, Schwabe G, Johansson A. Protection against exercise-induced bronchoconstriction during regular treatment with formoterol Turbuhaler(r) b.i.d. in adult asthmatics. Eur Resp J 1999; ERS-99 (P1085). Wallin A, Sandstrom T, Rosenhall L, Melander B. Time course and duration of bronchodilatation with formoterol dry powder in patients with stable asthma. Thorax 1993; 48:611-614. Correction Thorax 1993; 48:1188. Letters to the Editor Thorax 1994; 49:95. Wegener T, Hedenstrom H, Melander B. Rapid onset of action of inhaled formoterol in asthmatic patients. Chest 1992; 102:535-538.