Berotec Inhalation Solution (Fenoterol HBr)

BEROTEC® Inhalation Solution

Boehringer Ingelheim

Fenoterol HBr

Bronchodilator

Action And Clinical Pharmacology: The bronchodilating effect of fenoterol is produced primarily by stimulation of b2-receptors in the bronchial smooth muscles. The effect has been measured by means of spirometry (FEV1, FVC, MMFR), peak flow rates, flow volume curves, airway resistance (plethysmography) and oscillation mechanics.

Fenoterol, when administered by inhalation, exerts a significant increase in pulmonary function 5 minutes after administration and maximal effect in 30 to 60 minutes. This effect remains at the same level for 2 to 3 hours before gradually declining. A significant degree of bronchodilation has been detected in some studies for 6 to 8 hours.

Pharmacokinetics: In man, fenoterol is rapidly absorbed from the gastrointestinal tract, with an absorption level of 60%. After administration of tritium labelled fenoterol, peak plasma levels (2.5% of the oral dose) are reached in 2 hours, the half-life of radioactivity being 6 to 7 hours. When given from a pressurized container, absorption proceeds in 2 phases: the first one is essentially independent of the dose and apparently takes place between the first and fourth subdivision of the bronchial tree. A second phase appears to be identical to oral absorption. After inhalation, blood levels remain almost unchanged for 7 hours (0.3 to 0.4 ng/mL fenoterol).

Following inhalation, depending upon the method of inhalation and the system used, about 10 to 30% of the active ingredient released from the aerosol preparation reaches the lower respiratory tract, whereas the remainder is deposited in the upper respiratory tract and in the mouth. As a result, some of the fenoterol, which has been administered by inhalation, enters the gastrointestinal tract. After inhalation of one puff from a fenoterol metered aerosol, an absorption rate of 17% of the dose has been determined. Absorption then follows a biphasic course, 30% of fenoterol being rapidly absorbed with a half-life of 120 minutes.

Following i.v. administration, fenoterol is very rapidly taken up by the tissues where it is conjugated to the extent of 99% (as sulfates). Unlike isoproterenol, fenoterol is not metabolized by catechol-O-methyl transferase. The resulting metabolites are excreted via the kidneys (40% within 48 hours after oral administration) and the bile (fecal excretion: 40% of the oral dose).

Autoradiographic studies in gravid rats showed no detectable amounts of fenoterol in the fetus. Direct blood and tissue studies in several animal species and in man showed that the levels of fenoterol and its conjugates were 10 to 20 times lower in the fetus than in the maternal tissues.

Indications And Clinical Uses: For the treatment of acute severe bronchospasm, e.g. acute exacerbations of bronchial asthma or of severe chronic bronchitis. Fenoterol solution should be administered only by means of ultrasonic, motorized or compressed air nebulizers or in conjunction with intermittent positive pressure ventilation where IPPV is indicated.

Contra-Indications: Like other sympathomimetic amines, fenoterol should not be used in patients with tachyarrhythmias, hypertrophic obstructive cardiomyopathy, or in those with known hypersensitivity to fenoterol or to any of the product components (see Supplied).

Manufacturers’ Warnings In Clinical States: Like other B2-agonist inhalation solutions, fenoterol should not be used on a regular daily basis without appropriate concomitant anti-inflammatory therapy (see Dosage).

Children: Not currently indicated for use in children under 12 years of age as the dosing regimen and evidence concerning its safety in this age group have not been established.

Pregnancy and Lactation: The safety of fenoterol in pregnancy and lactation has not been established. b2-agonists should be used with caution before childbirth in view of their inhibiting effect on uterine contractions.

General: Care should be taken in patients suffering from myocardial insufficiency, cardiac arrhythmias, recent myocardial infarction, severe organic heart and/or other vascular disorders, hypertension, hyperthyroidism, pheochromocytoma or diabetes mellitus.

Fatalities, the exact cause of which is unknown, have been reported following excessive use of sympathomimetic amines by inhalation. Cardiac arrest was noticed in several instances.

Some patients receiving inhaled b-adrenergic agonists have developed severe paradoxical bronchospasm, which has been life-threatening. The cause of this refractory state is unknown. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.

Fenoterol solution in 20 mL bottles contains preservatives (benzalkonium chloride and edetate disodium) which may cause bronchoconstriction in some patients with hyperreactive airways.

The 2 mL unit dose vial does not contain preservatives.

In common with other b-adrenergic agents, fenoterol can induce reversible metabolic changes. These are most pronounced during infusions of the drug and include hyperglycemia and hypokalemia.

Potentially serious hypokalemia may result from b2-agonist therapy, mainly from parenteral and nebulized administration. Particular caution is advised in acute severe asthma as hypokalemia may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics; the adverse effects of hypokalemia may be exacerbated by hypoxia. It is recommended that serum potassium levels be monitored in such situations. Hypokalemia will increase the susceptibility of digitalis-treated patients to cardiac arrhythmias.

The bronchodilating action of sympathomimetic drugs may be antagonized by b-adrenergic blocking agents with the result that the respiratory status of patients may worsen when the 2 drugs are used concomitantly. In patients requiring concomitant treatment with fenoterol and a b-adrenergic blocking agent, the use of a relatively cardioselective b-blocker (e.g. metoprolol, atenolol, acebutolol) must be considered. During concomitant treatment, patients should be monitored carefully for possible deterioration in pulmonary function or for the need to adjust the dosage of either drug.

Fenoterol Solution in Conjunction with IPPV: It has been reported in several cases that the use of intermittent positive-pressure ventilation in acute asthma attacks was related to lethal episodes of hypoxia and pneumothorax. This method of drug administration may be ineffective in patients with severe obstruction and greatly increased airway resistance and it may induce severe hypercapnia and hypoxia. During intermittent positive-pressure ventilation therapy, the monitoring of arterial blood gases is highly desirable.

Precautions: Fenoterol solution is intended only for inhalation with suitable nebulizing devices and should not be taken orally or administered parenterally.

Instruct your patients to seek medical advice if therapy does not produce a significant improvement or if the patient’s condition gets worse in order to determine a new plan of treatment. Instruct your patients to consult a doctor immediately in the case of acute or rapidly worsening dyspnea.

Increasing use of b2 agonists to control symptoms of bronchial obstruction, especially administration on a regular basis or in high amounts, indicates deterioration of asthma control. Under these conditions, the patient’s therapy plan has to be revised. It is inadequate simply to increase the use of bronchodilators under these circumstances, in particular over extended periods of time (see Dosage).

Concomitant use of fenoterol with other sympathomimetic agents is not recommended since the combined use may lead to deleterious cardiovascular effects. If concomitant use is necessary, this should take place only under strict medical supervision.

Fenoterol should be used with caution in asthmatic or emphysematous patients who also have acute and recurring congestive heart failure or glaucoma or in patients sensitive to sympathomimetic amines.

On-demand (symptom-oriented) treatment may be preferable to regular use. Patients should be evaluated for the addition or the increase of anti-inflammatory therapy (e.g., inhaled corticosteroids) to control airway inflammation and to prevent long term lung damage.

Three retrospective case-control studies, from one group in New Zealand, have suggested that there may be an increased risk of death in those patients using Berotec whom the studies classified as severe asthmatics. These conclusions have not been confirmed by other studies and are subject to considerable debate and ongoing studies.

To ensure the proper dosage administration, the patient should be instructed by the physician or other health professional on the proper use and maintenance of the nebulizer.

Drug Interactions: Other b-adrenergic agents, anticholinergics, xanthine derivatives (such as theophylline) and corticosteroids may enhance the effect of fenoterol. Avoid concomitant use of fenoterol with MAO inhibitors, tricyclic antidepressants or with other sympathomimetic agents since their combined effect on the cardiovascular system may be deleterious to the patient.

b-receptor blocking agents and fenoterol inhibit the effect of one another (see Warnings).

Concomitant anti-inflammatory therapy should be considered for patients with bronchial asthma and steroid responsive chronic obstructive pulmonary disease.

Inhalation of halogenated hydrocarbon anesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of b-agonists.

Labor and Delivery: Beta-adrenergic agents have been shown to delay preterm labor in some reports. There are no well controlled studies which demonstrate that such agents will stop preterm labor or prevent labor at term. Cautious use of b-adrenergics for the relief of bronchospasm is therefore required in pregnant patients to avoid interference with uterine contractility.

Adverse Reactions: At the most frequently used dosage of fenoterol of 0.5 to 1 mg, tremor occurred in 12% of patients. At higher doses of fenoterol solution (up to 2.5 mg) given for the treatment of severe asthma in a hospital emergency room, mild to moderate tremor occurred in 32% of patients. Other adverse reactions in decreasing order of frequency included nervousness, dizziness, headache, lightheadedness, and palpitations.

In 104 patients who received the highest recommended dosage of 2.5 mg of fenoterol, increases in heart rate of 10% or greater within 4 hours after drug administration were observed in 21% of the patients. However, at least an equal number of patients had decreased heart rate of a similar magnitude in the same time period. The remainder showed no significant pulse rate changes.

As with other b-mimetics, nausea, vomiting, sweating, weakness, and myalgia/muscle cramps may occur. In rare cases, decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmia, particularly after higher doses, may occur.

Local irritation or allergic reactions have been reported rarely. As with other bronchodilators, cough and, very rarely, paradoxical bronchospasm have been observed (see Warnings). Potentially serious hypokalemia may result from b2-agonist therapy.

In individual cases, psychological alterations have been reported under inhalational therapy with b-mimetics.

Symptoms And Treatment Of Overdose: Symptoms: Overdosage resulting in excessive b-adrenergic stimulation (including exaggeration of the known pharmacological effects, i.e., any of the symptoms listed under adverse reactions) may cause flushing, palpitations, tremor, hypotension, widening of pulse pressure, anginal pain, tachycardia, arrhythmias, hypertension, and in extreme cases, sudden death.

Treatment: Symptomatic: Cardiac and respiratory support should be provided as required. If needed to antagonize the effect of b-adrenergic stimulation, the use of a b-adrenergic blocking agent, preferably one of the relatively cardioselective ones (e.g., metoprolol, atenolol, acebutolol) may be considered, bearing in mind, however, the potential danger of inducing an asthmatic attack. Administration of sedatives or tranquilizers may be appropriate in severe cases.

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

Fenoterol solution should be used only under medical supervision. On prolonged use, patients should be evaluated for the addition or the increase of anti-inflammatory therapy (e.g., inhaled corticosteroids) to control airway inflammation and to prevent long-term lung damage.

In most cases, dilution of the dose with sterile preservative-free saline is not necessary. However, volumes of fenoterol solution less than 2 mL are not appropriate for nebulization and must be diluted with saline or another suitable nebulizer solution to make-up a total fill volume of 2 to 5 mL.

Motorized, Compressed Air or Ultrasonic Nebulizers: These nebulizers generate low pressure, low velocity aerosols. The average single dose is 0.5 to 1 mg of fenoterol. In more refractory cases, up to 2.5 mg of fenoterol may be given. Optimal deposition in the lungs is achieved with the patient breathing quietly and slowly. Treatment may be repeated every 6 hours if necessary.

Intermittent Positive Pressure Ventilation: Fenoterol solution may be used in conjunction with Intermittent Positive Pressure Ventilation (IPPV) when such therapy is indicated (see Warnings). The average single dose is 0.5 to 1 mg of fenoterol. In more refractory cases, up to 2.5 mg of fenoterol may be given. The inspiratory pressure is usually 10 to 20 cm H2O and optimal deposition of the drug in the lungs is achieved with the patient breathing quietly and slowly. Treatment may be repeated every 6 hours if necessary.

If a previously effective dosage regimen fails to provide the usual relief, or the effects of a dose last for less than 3 hours, medical advice should be sought immediately; this is a sign of seriously worsening asthma that requires reassessment of therapy.

In accordance with the present practice for asthma treatment, concomitant anti-inflammatory therapy should be part of the regimen if fenoterol inhalation solution needs to be used on a regular daily basis.

Stability and Storage: Bottles: The undiluted solution in its original, unopened amber glass bottle may be stored at room temperature (approximately 25°C) and will be stable up to the expiration date stamped on the label.

The undiluted solution in its original amber glass bottle, opened and tightly recapped several times , may be stored at room temperature (approximately 25°C) for 30 days.

The solution, diluted with preservative-free, sterile sodium chloride inhalation solution, USP 0.9% (normal saline) may be stored at room temperature (approximately 25°C) for 24 hours.

The effects of refrigeration on the stability of undiluted or diluted solution is not known.

Controlled laboratory experiments using a mixture of fenoterol solution with ipratropium solution diluted with a sterile bacteriostatic sodium chloride 0.9% preserved with benzalkonium chloride (i.e., preserved normal saline), indicated that such a mixture was stable for 7 days at room temperature. For the preparation of such a mixture, it is recommended that only sterile solutions of bacteriostatic sodium chloride 0.9% preserved with 0.01% benzalkonium chloride be used to maintain the level of preservative in the mixture.

The safety of saline-preservatives other than benzalkonium chloride has not been established.

Unit Dose Vials: Unopened unit dose vials of fenoterol solution should be stored at controlled room temperature (approximately 25°C) and protected from heat and light. If required, the solution should be diluted with a preservative-free sterile sodium chloride solution 0.9% and used immediately. Any solution remaining in the vial must be discarded.

The physicial compatibility of fenoterol solution in unit dose vials with other inhalation solutions will not be affected by the absence of preservatives from the solution. If a mixture is prepared, dilute the mixture with preservative free sterile sodium chloride solution 0.9% and use immediately.

Any unused portion of such combined solutions must be discarded.

Availability And Storage: Bottles: Each mL of aqueous solution contains: fenoterol HBr 1 mg. Nonmedicinal ingredients: benzalkonium chloride and edetate disodium in an aqueous solution.

Unit Dose Vials: 0.625 mg/mL: Each mL of aqueous solution contains: fenoterol HBr 0.625 mg. Nonmedicinal ingredients: hydrochloric acid, sodium chloride and water. Plastic single use vials of 2 mL.

0.25 mg/mL: Each mL of aqueous solution contains: fenoterol HBr 0.25 mg. Nonmedicinal ingredients: hydrochloric acid, sodium chloride and water. Plastic single use vials of 2 mL.

BEROTEC® Inhalation Solution Boehringer Ingelheim Fenoterol HBr Bronchodilator

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