Berodual/Berodual Forte

Berodual/Berodual Forte Mechanism of Action

ipratropium + fenoterol

Manufacturer:

Boehringer Ingelheim

Distributor:

Zuellig Pharma
Full Prescribing Info
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.
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