Berodual/Berodual Forte

Berodual/Berodual Forte

ipratropium + fenoterol

Manufacturer:

Boehringer Ingelheim

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ipratropium bromide, fenoterol HBr.
Description
Each Berodual metered dose (puff) contains ipratropium bromide 21 mcg, corresponding to anhydrous ipratropium bromide 20 mcg and fenoterol HBr 50 mcg. It also contains anhydrous citric acid, purified water and absolute ethanol as excipients, and 1, 1, 1, 2-tetrafluoroethane (HFA 134a) as propellant.
Each mL (= 20 drops) of Berodual solution contains ipratropium bromide 261 mcg, corresponding to anhydrous ipratropium bromide 250 mcg and fenoterol HBr 500 mcg. It also contains benzalkonium chloride, disodium edetate, sodium chloride and hydrochloric acid as excipients.
Each unit-dose vial of Berodual Forte solution for inhalation contains ipratropium bromide 520 mcg, corresponding to anhydrous ipratropium bromide 500 mcg and fenoterol HBr 1250 mcg. It also contains sodium chloride and hydrochloric acid as excipients.
Ipratropium bromide is (8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate.
Fenoterol HBr is 1-(3,5-dihydroxy-phenyl)-2-[1-(4-hydroxy-benzyl)-ethyl]-amino-ethanol hydrobromide.
Action
Trials with treatment duration of up to 3 months involving adult asthmatics and COPD patients, and asthmatic children, in which the HFA formulation and the CFC formulation have been compared, have shown the 2 formulations to be therapeutically equivalent.
Pharmacology: Berodual/Forte contains 2 active bronchodilating ingredients: Ipratropium bromide, exhibiting an anticholinergic effect and fenoterol HBr, a β-adrenergic agent.
Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it inhibits vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one.
In controlled up to 90-day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in pulmonary function (FEV1 and FEF25-75% increases of ≥15%) occurred within 15 min, reached a peak in 1-2 hrs, and persisted in the majority of patients up to 6 hrs.
In controlled up to 90-day studies in patients with bronchospasm associated with asthma, significant improvements in pulmonary function (FEV1 increases of ≥15%) occurred in 40% of the patients.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
Fenoterol HBr is a direct-acting sympathomimetic agent, selectively stimulating β2-receptors in the therapeutic dose range. The stimulation of β1-receptors comes into effect at a higher dose range. Occupation of β2-receptors activates adenyl cyclase via a stimulatory Gs-protein. The increase in cyclic AMP activates protein kinase A which then phosphorylates target proteins in smooth muscle cells. This in turn leads to the phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and the opening of large-conductance calcium-activated potassium channels.
Fenoterol relaxes bronchial and vascular smooth muscle and protects against bronchoconstricting stimuli eg, histamine, methacholine, cold air and allergen (early response). After acute administration, the release of bronchoconstricting and pro-inflammatory mediators from mast cells is inhibited. Further, an increase in mucociliary clearance has been demonstrated after administration of higher doses of fenoterol.
Higher plasma concentrations, which are more frequently achieved with oral, or even more so, with IV administration inhibit uterine motility. Also at higher doses, metabolic effects are observed: Lipolysis, glycogenolysis, hyperglycemia and hypokalemia, the latter caused by increased K+-uptake primarily into skeletal muscle. Beta-adrenergic effects on the heart eg, increase in heart rate and contractility, are caused by the vascular effects of fenoterol, cardiac β2-receptor stimulation, and at supratherapeutic doses by β1-receptor stimulation. As with other β-adrenergic agents, QTc prolongations have been reported. For fenoterol, these were discrete and observed at doses higher than recommended. The clinical significance has not been established. Tremor is a more frequently observed effect of β-agonists. Unlike the effects on the bronchial smooth muscle, the systemic effects of β-agonists are subject to the development of tolerance.
In clinical studies, fenoterol was shown to be highly efficacious in manifest bronchospasm. It prevents bronchoconstriction following exposure to various stimuli eg, exercise, cold air and the early response following allergen exposure.
Concurrent use of these 2 active ingredients dilates the bronchi by affecting different pharmacological sites of action. The 2 active substances thus complement each other in their spasmolytic action on the bronchial muscles and allow a broad therapeutic use in the field of bronchopulmonary disorders associated with constriction of the respiratory tract.
The complementary action is such that only a very low proportion of the β-adrenergic component is needed to obtain the desired effect, facilitating individual dosage suited to each patient with a minimum of adverse reactions.
In patients with asthma and with chronic obstructive pulmonary disorder (COPD), Berodual/Forte has been shown to be as efficacious as double the dose of fenoterol administered without ipratropium but was better tolerated in cumulative dose-response studies. In adequately-sized studies in patients with asthma and COPD, better efficacy compared to its components ipratropium or fenoterol was demonstrated.
In acute asthma, the combination of fenoterol and ipratropium is effective shortly after administration and has been shown to be more efficacious than each of its components.
In acute bronchoconstriction, Berodual is effective shortly after administration and is therefore also suitable for treating acute attacks of asthma.
Pharmacokinetics: The therapeutic effect of Berodual is produced by a topical action in the airway. The pharmacodynamics of the bronchodilation produced by Berodual are therefore not relevant to the pharmacokinetics of the active constituents of the preparation. Pharmacokinetic investigation has shown, however, that the HFA formulation and the conventional CFC formulation can be considered equivalent.
About 16% of the dose is deposited in the respiratory tract following inhalation by metered aerosol. The remaining portion is being swallowed.
Fenoterol HBr and ipratropium bromide are absorbed very quickly from the respiratory tract. The peak plasma concentrations are reached only minutes after inhalation.
There is no evidence that the pharmacokinetics of both ingredients in the combination differ from those of the mono-substance.
Fenoterol HBr: The swallowed portion is mainly metabolized to sulfate conjugates. The absolute bioavailability following oral administration is low (approximately 1.5%). Following IV administration, 3 phases were observed, whereby the terminal half-life was approximately 3 hrs. Fenoterol and its conjugates are rapidly excreted renally (renal clearance: 267 mL/min). About 40% of the drug is bound to plasma proteins. In its nonmetabolized state, fenoterol HBr can slowly pass through the placenta and enter the maternal milk.
Ipratropium Bromide: The absolute bioavailability after oral administration is low (approximately 2%). Following IV administration, a rapid biphasic decline in plasma is noted for ipratropium. The terminal half-life was about 1.6 hrs. The total clearance of the active ingredient is 2.3 L/min. Approximately 40% of the clearance is renal (0.9 L/min) and 60% nonrenal ie, mainly hepatometabolic. The main metabolites found in urine bind poorly to the muscarinic receptor. Forty-six percent (46%) of the active ingredient are excreted renally after IV administration, 4.4-13.1% after inhalation from a metered-dose inhaler are excreted as unchanged compound in urine.
The drug is minimally (<20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier. It is not known if the placental barrier is crossed.
Toxicology: Toxicity studies with repeated doses of Berodual have shown the toxicological profiles of the HFA formulation and the conventional CFC formulation to be similar.
In the acute toxicology studies with Berodual/Forte in a ratio of 1:2.5 (ipratropium bromide:fenoterol HBr) in mice and rats using oral, IV and inhalation routes, the LD50 values revealed a low index of toxicity. They were determined more by the ipratropium bromide component than fenoterol HBr without any indication of potentiation.
After IV administration of Berodual/Forte in dogs and inhalation administration in rats and dogs of up to 4 weeks, only minor toxic effects at concentrations up to several hundred times greater than that recommended in man were observed. Left ventricular myocardial scars were seen in only 1 animal from the highest treatment group of the IV dog study (84 mcg/kg/day). Thirteen-week studies in rats by oral and in beagle dogs by inhalation administration of Berodual/Forte did not show any toxicological changes beyond that proportional to the individual components.
All of the toxicological systems appeared to be substance-related and were well-known out of the documentation of fenoterol HBr and ipratropium bromide. There was no indication of potentiation when ipratropium bromide and fenoterol HBr were administered concomitantly.
After inhalation administration of Berodual/Forte in rats and rabbits, no teratogenic effects occurred. Also, no teratogenic effects were seen after ipratropium bromide and after fenoterol HBr, only after administration of extremely high (toxic) doses.
Genotoxicity and carcinogenicity studies were not conducted with Berodual/Forte. But in vitro and in vivo assays revealed that neither fenoterol HBr nor ipratropium bromide have a mutagenic potential.
Besides carcinogenicity, studies over 2 years with inhalation administration of fenoterol HBr in rats with doses up to 2 mg/kg/day and with oral administration of ipratropium bromide in mice and rats with doses up to 6 mg/kg/day revealed no pathological effects.
After oral administration of very high doses of fenoterol HBr (25 mg/kg/day), uterine leiomyoma in mice and mesovarian leiomyoma in rats occurred. These results can be explained by the pharmacodynamic effects of this type of compound at the β-receptors of the uterine smooth muscle.
Epidemiologically, there is no indication that comparable tumors develop in humans under therapeutic conditions.
Berodual HFA and CFC have been shown to be equally well-tolerated in the respiratory tract.
Indications/Uses
As a bronchodilator for the prevention and treatment of symptoms in chronic obstructive airway disorders with reversible bronchospasm eg, bronchial asthma and especially chronic bronchitis with or without emphysema. Concomitant anti-inflammatory therapy should be considered for patients with bronchial asthma and steroid-responsive chronic obstructive pulmonary disease (COPD).
Dosage/Direction for Use
The dosage should be adapted to the individual requirements; patients should also be kept under medical observation during treatment. Unless otherwise prescribed, the following dosages are recommended.
Berodual: Metered-Dose Inhaler: Adults and Children >6 years: Acute Asthma Episodes: 2 puffs are sufficient for prompt symptom relief in many cases. In more severe cases, if breathing has not noticeably improved after 5 min, 2 further puffs may be taken.
If an attack has not been relieved by 4 puffs, further puffs may be required. In these cases, patients should consult the doctor or the nearest hospital immediately.
Intermittent and Long-Term Treatment: 1-2 puffs for each administration, up to a maximum of 8 puffs/day (average 1-2 puffs 3 times daily).
In children, Berodual metered aerosol should only be used on medical advice and under the supervision of an adult.
Solution: Acute Asthma Episodes: Adults (Including the Elderly) and Adolescents >12 years: 1 mL (20 drops) is sufficient for prompt symptom relief in many cases of mild to moderate exacerbations.
In particular severe cases eg, for patients in the emergency room not responding to the doses mentioned, higher doses up to 2.5 mL (50 drops) may be required.
For particular severe cases, up to 4 mL (80 drops) may be administered under medical supervision.
Intermittent and Long-Term Treatment: If repeated dosing is required, 1-2 mL (20-40 drops) for each administration, up to 4 times daily.
In cases of moderate bronchospasm or with assisted ventilation, a dose in the lower range of 0.5 mL (10 drops) is recommended.
Children 6-12 years: 0.5-1 mL (10-20 drops) is sufficient for prompt symptom relief in many cases.
In severe cases, higher doses up to 2 mL (40 drops) may be required.
For particular severe cases, up to 3 mL (60 drops) may be administered under medical supervision.
Intermittent and Long-Term Treatment: If repeated dosing is required, 0.5-1 mL (10-20 drops) for each administration, up to 4 times daily.
In cases of moderate bronchospasm or with assisted ventilation, a dose in the lower range of 0.5 mL (10 drops) is recommended.
Children <6 years (<22 kg body weight):
Because there is limited information in this age group, the following dose is recommended to be given under medical supervision only:
About 25 mcg ipratropium bromide and 50 mcg fenoterol HBr per kg body weight per dose up to 0.5 mL (10 drops) up to 3 times daily.
Treatment should usually be started with the lowest recommended dose.
The recommended dose is to be diluted with physiological saline to a final volume of 3-4 mL and nebulized and inhaled until the solution is consumed.
Berodual solution may, however, not be diluted with distilled water.
The solution should be re-diluted each time before use; any residual diluted solution should be discarded.
Dosage may be dependent upon the mode of inhalation and the quality of the nebulization. The duration of inhalation can be controlled by the dilution volume.
Berodual solution can be administered using a range of commercially available nebulizing devices. Where wall oxygen is available, the solution is best administered at a flow rate of 6-8 L/min.
The dose may be repeated after intervals of at least 4 hrs, if required.
Berodual Forte: The solution is ready for use and requires no dilution.
Adults (Including the Elderly) and Children >12 years: Acute Asthma Episodes: 1 unit-dose vial is sufficient for prompt symptom relief in most cases, typically the hospital-based treatment of moderate to severe asthma attacks or the home- and hospital-based treatment of patients with moderate to severe COPD. If in very severe cases, 2 unit-dose vials are required for symptom relief, these should be administered under medical supervision.
Intermittent and Long-Term Treatment: 1 unit-dose vial up to 4 times daily.
Berodual Forte can be administered using a range of commercially available nebulizing devices. Where wall oxygen is available, the solution is best administered at a flow rate of 6-8 L/min.
Administration: Metered-Dose Inhaler: Instruction for Use: The correct administration of the metered-dose inhaler apparatus is essential for successful therapy.
Depress the valve twice before the metered aerosol is used for the first time.
Before each use, the following rules should be observed:
Remove the protective cap. Breathe out deeply. Hold the metered-dose inhaler and close lips around the mouthpiece. The arrow and the base of the container should be pointing upwards.
Breathe in as deeply as possible, pressing the base of the container firmly at the same time; this releases 1 metered dose. Hold the breath for a few seconds, then remove the mouthpiece from the mouth and breathe out.
The same action should be repeated for a 2nd inhalation.
Replace the protective cap after use.
If the metered aerosol has not been used for >3 days, the valve has to be actuated once.
The mouthpiece should always be kept clean and can be washed with warm water. If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clean water.
Warning: The plastic mouthpiece has been specially designed for use with Berodual to ensure that the right amount of the medicine is delivered. The mouthpiece must never be used with any other aerosol nor must the Berodual metered aerosol be used with any mouthpiece other than the one supplied with the product.
The container is under pressure and should by no account be opened by force or exposed to temperatures above 50°C.
The solution is intended only for inhalation with suitable nebulizing devices and should not be taken orally. The diluted solution should be inhaled directly after preparation of the solution. Patients should follow the instructions provided by the manufacturer of the nebulizing device for proper care, maintenance and cleaning of the equipment.
Solution: The unit-dose vials are intended only for inhalation with suitable nebulizing devices and should not be taken orally or administered parenterally.
Prepare the nebulizer for filling, according to the instructions provided by the manufacturer or doctor.
Tear 1 unit-dose vial from the strip.
Open the unit-dose vial by firmly twisting the top.
Squeeze the contents of the unit-dose vial into the nebulizer reservoir.
Assemble the nebulizer and use as directed.
After use, throw away any solution left in the reservoir and clean the nebulizer, following the manufacturer's instructions.
Overdosage
Symptoms: The effects of overdosage are expected to be primarily related to fenoterol.
The expected symptoms with overdosage are those of excessive β-adrenergic stimulation, the most prominent being tachycardia, palpitation, tremor, hypertension, hypotension, widening of the pulse pressure, anginal pain, arrhythmias and flushing.
Expected symptoms of overdosage with ipratropium bromide (eg, dry mouth, visual accommodation disturbances) are mild because the systemic availability of inhaled ipratropium is very low.
Treatment: Administration of sedatives, tranquilizers, in severe cases intensive therapy.
Beta-receptor blockers, preferably β1-selective, are suitable as specific antidotes; however, a possible increase in bronchial obstruction must be taken into account and the dose should be adjusted carefully in patients suffering from bronchial asthma or COPD because of the risk of precipitating severe bronchospasm, which may be fatal.
Contraindications
Hypertrophic obstructive cardiomyopathy and tachyarrhythmia. Hypersensitivity to fenoterol HBr or atropine-like substances, or to any of the excipients of Berodual/Forte.
Special Precautions
When using the new formulation of Berodual metered aerosol for the first time, some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Patients should be made aware of this when changing from one formulation to the other. They should also be told that the formulations have been shown to be interchangeable for all practical purposes and that the difference in taste has no consequences in terms of the safety or the efficacy of the new formulation.
In the case of acute, rapidly worsening dyspnea (difficulty in breathing), a doctor should be consulted immediately.
Prolonged Use: In patients with bronchial asthma and mild COPD, on demand (symptom-oriented) treatment may be preferable to regular use.
The addition or the increase of anti-inflammatory therapy to control airway inflammation and to prevent deterioration of disease control should be considered for patients with bronchial asthma and with steroid-responsive COPD.
The use of increasing amounts of β2-agonists-containing products on a regular basis to control symptoms of bronchial obstruction may suggest declining disease control. If bronchial obstruction deteriorates, it is inappropriate and possibly hazardous to simply increase the use of β2-agonist-containing products beyond the recommended dose over extended periods of time. In this situation, the patient's therapy plan, and in particular, the adequacy of anti-inflammatory therapy with inhaled corticosteroids, should be reviewed to prevent potentially life-threatening deterioration of disease control. Other sympathomimetic bronchodilators should only be used with Berodual/Forte under medical supervision.
In the following conditions, Berodual/Forte should only be used after careful risk/benefit assessment, especially when doses higher than recommended are used: Insufficiently controlled diabetes mellitus, recent myocardial infarction, severe organic heart or vascular disorders, hyperthyroidism, pheochromocytoma.
Potentially serious hypokalemia may result from β2-agonist therapy.
Berodual/Forte should be used with caution in patients with prostatic hyperplasia or bladder-neck obstruction or predisposed to narrow-angle glaucoma.
There have been isolated reports of ocular complications (ie, mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolized ipratropium bromide either alone or in combination with an adrenergic β2-agonist was sprayed into the eyes. Thus, patients must be instructed in the correct administration of Berodual metered aerosol. Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist's advice sought immediately.
Patients must be instructed in the correct administration of Berodual/Forte solution. Care must be taken not to allow the solution or mist to enter into the eyes. It is recommended that the nebulized solution be administered via a mouthpiece. If this is not available and a nebulizer mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.
Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.
Immediate hypersensitivity reactions may occur after administration of Berodual/Forte, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal edema and anaphylaxis.
Use in Pregnancy & Lactation: Preclinical data, combined with available experience in humans have shown no evidence of ill-effects in pregnancy of fenoterol or ipratropium. Nonetheless, the usual precautions regarding the use of drugs during pregnancy, especially during the 1st trimester, should be exercised.
The inhibitory effect of fenoterol on uterine contraction should be taken into account.
Preclinical studies have shown that fenoterol HBr is excreted into breast milk. It is not known whether ipratropium is excreted in breast milk. But it is unlikely that ipratropium would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted in breast milk, caution should be exercised when Berodual/Forte is administered to a nursing woman.
Use in Children: Berodual metered-dose inhaler should only be used on medical advice and under the supervision of an adult. Because of insufficient information, the general use of Berodual Forte in children <12 years is not recommended.
Use In Pregnancy & Lactation
Use in Pregnancy & Lactation: Preclinical data, combined with available experience in humans have shown no evidence of ill-effects in pregnancy of fenoterol or ipratropium. Nonetheless, the usual precautions regarding the use of drugs during pregnancy, especially during the 1st trimester, should be exercised.
The inhibitory effect of fenoterol on uterine contraction should be taken into account.
Preclinical studies have shown that fenoterol HBr is excreted into breast milk. It is not known whether ipratropium is excreted in breast milk. But it is unlikely that ipratropium would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted in breast milk, caution should be exercised when Berodual/Forte is administered to a nursing woman.
Side Effects
Undesirable effects of Berodual/Forte are nervousness, dry mouth, headache, dizziness and fine tremor of skeletal muscles. Tachycardia, increased heart rate and palpitations may occur. Gastrointestinal motility disturbances (eg, vomiting, constipation, diarrhea) and urinary retention albeit reversible have been reported.
Ocular side effects (including accommodation disturbances and glaucoma) may occur (see Precautions). Skin reactions or allergic-type reactions eg, skin rash, angioedema of the tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions have been reported.
Potentially serious hypokalemia may result from β2-agonist therapy.
As with other β-agonist-containing products, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur.
Decrease in diastolic blood pressure and increase in systolic blood pressure have been observed. Arrhythmias (particularly after higher doses), atrial fibrillation and supraventricular tachycardia may occur.
In individual cases, psychological alterations have been reported under inhalational therapy with β-agonist-containing products.
As with use of other inhalation therapy, cough, local irritation (eg, pharyngitis, throat irritation) and inhalation-induced bronchospasm have been reported.
Drug Interactions
Other β-adrenergics, anticholinergics and xanthine derivatives (eg, theophylline) may enhance the bronchodilatory effect. The concurrent administration of other β-mimetics, systemically available anticholinergics and xanthine derivatives (eg, theophylline) may increase the adverse reactions.
A potentially serious reduction in bronchodilation may occur during concurrent administration of β-blockers.
Beta-agonist-induced hypokalemia may be increased by concomitant treatment with xanthine derivatives, corticosteroids and diuretics. This should be taken into account particularly in patients with severe airway obstruction.
Hypokalemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin. Additionally, hypoxia may aggravate the effects of hypokalemia on cardiac rhythm. It is recommended that serum potassium levels are monitored in such situations.
Beta2-agonists containing medicinal products should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of β-adrenergic agonists may be enhanced.
Inhalation of halogenated hydrocarbon anesthetics eg, halothane, trichloroethylene and enflurane may increase the susceptibility on the cardiovascular effects of β-agonists.
Caution For Usage
Berodual: The container is under pressure and should on no account be opened by force or exposed to temperatures exceeding 50°C. As the metered aerosol container is not transparent, it is not possible to see when it is empty. When 200 doses (puffs) have all been used, the aerosol may still appear to contain a small amount of fluid. The aerosol should, however, be replaced because the patient may not get the right amount of treatment.
Berodual Forte: Since Berodual Forte contains no preservative, it is important that the contents are used soon after opening and that a fresh vial is used for each administration to avoid microbial contamination. Partly used, opened or damaged unit-dose vials should be discarded.
ATC Classification
R03AL01 - fenoterol and ipratropium bromide ; Belongs to the class of combination of adrenergics with anticholinergics, that may also include a corticosteroid. Used in the treatment of obstructive airway diseases.
Presentation/Packing
Berodual: Metered-dose inhaler (MDI) 200 puffs/10 mL (with mouthpiece). Soln 20 mL (in dropper bottle).
Berodual Forte: Unit dose vial (UDV) 4 mL x 20's.
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