Ipratropium bromide, fenoterol HBr.
Berodual MDI: Each metered dose (puff) contains ipratropium bromide 21 mcg corresponding to anhydrous ipratropium bromide 20 mcg and fenoterol HBr 50 mcg.
Berodual F UDV: Each unit-dose vial (4 mL) solution for inhalation contains ipratropium bromide 0.52 mg corresponding to anhydrous ipratropium bromide 0.5 mg and fenoterol HBr 1.25 mg.
Berodual metered-dose inhaler also contains soya lecithin.
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.
Pharmacology: Berodual/F UDV 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 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 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 muscles 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. 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 COPD, Berodual inhalation solution has been shown to be an efficacious bronchodilator not only after acute but also after chronic administration.
In patients with asthma and with COPD, studies with the metered aerosol have shown that Berodual is as efficacious as double the dose of fenoterol administered without ipratropium but is 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, in the majority of studies, 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.
The effect of 4-times-daily domiciliary nebulized Berodual F UDV for 3 weeks was assessed in a placebo-controlled, randomized, double-blind, crossover study in 20 patients with a low bronchodilator response and steroid-resistant chronic obstructive pulmonary disease. Home expiratory flow rate rose from 164 L/min on saline to 196 L/min on Berodual F UDV. Secondary endpoint analysis revealed a fall in home inhaler usage and a rise in visual analogue scales for symptoms.
Pharmacokinetics: About 16% of the dose is deposited in the respiratory tract following inhalational administration. 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 combination differ from those of the mono-substance.
Fenoterol HBr: The swallowed portion is mainly metabolized to sulfate conjugates. The bioavailability following oral administration is low (approximately 1.5%). Following IV administration, 3 phases were observed, whereby the half-life of the terminal phase was approximately 3 hrs. Fenoterol and its conjugates are rapidly excreted renally (renal clearance: 267 mL/min). About 40-55% 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 bioavailability of the swallowed portion is low (approximately 2%). Following IV administration, a rapid biphasic decline in plasma is noted for ipratropium. The half-life of the terminal elimination phase 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. Renal excretion of the active ingredient is given as 46% of the dose after IV administration and 3-8% of the dose after oral inhalation. The swallowed portion is only poorly absorbed. The drug is minimally (<20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier or the placental barrier.
Toxicology: In the acute toxicology studies with Berodual/F UDV 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/F UDV in dogs and inhalative 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 inhalative administration of Berodual/F UDV did not show any toxicological changes beyond those 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.
Teratogenicity: After inhalative administration of Berodual/F UDV 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.
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).
The dosage should be adapted to the individual requirements; patient should also be kept under medical observation during treatment. Unless otherwise prescribed, the following dosages are recommended:
Berodual MDI: 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.
Berodual F UDV: 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 F UDV 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. Because of insufficient information, the general use in children <12 years is not recommended.
Administration: Berodual MDI: The correct administration of the metered aerosol is essential for successful therapy.
Shake the aerosol canister and depress the valve twice before the apparatus is used for the first time.
Before each use, the following rules should be observed: Remove protective cap. Shake the metered aerosol well before each use. Breathe-out deeply. Hold the metered aerosol and close lips over 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 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.
Special Instructions for the Use of the Inhalation Aid: Before each use, the following rules should be observed:
1. Remove protective cap.
2. Attach the inhalation aid with the appropriate opening to the mouthpiece of the metered aerosol.
3. Cover the other opening with the protective cap. The protective cap of the metered aerosol is to be attached to the inhalation aid in order to prevent premature leakage of the fine cloud of substance.
4. Hold the metered aerosol, with inhalation aid attached, between thumb and forefinger (arrow and container base pointing upwards) and shake well before each use.
5. Press the container base firmly to release a puff from the aerosol into the closed inhalation aid.
6. Remove the protective cap from the inhalation aid and, immediately after a normal exhalation, inhale the substance cloud from the inhalation aid. Breathe-in deeply. Hold breath for a few seconds.
If 2 puffs have been prescribed as a single dose, then the procedure described under points 4-6 must be repeated.
7. Remove the inhalation aid from the metered aerosol and replace the protective cap on the mouthpiece of the metered aerosol.
On Point 6: Inhalation from the inhalation aid must take place immediately after releasing the aerosol puff, otherwise, the released particles of active substance would very quickly settle on the inside surface of the device and thus lose their efficacy. Breath should be held for a few seconds to enable the substance cloud to settle in the bronchi, rather than be immediately exhaled.
If it is used correctly, the inhalation aid facilitates inhalation of the substance, allowing it to penetrate deep into the bronchial system. It thus relieves the user much more quickly of the frightening symptoms of dyspnea.
Berodual F UDV: 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.
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 and transient in nature, in view of the wide therapeutic range and topical administration.
Treatment: Administration of sedatives, tranquilizers and in severe cases, intensive therapy. β-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.
Hypertrophic obstructive cardiomyopathy, tachyarrhythmia. Hypersensitivity to fenoterol HBr or atropine-like substances or inactive ingredients of Berodual/F UDV.
Berodual metered aerosol should not be taken in patients with a history of hypersensitivity to soya lecithin or related food products eg, soybean and peanut.
In the case of acute, rapidly worsening dyspnea (difficulty in breathing), the 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-agonist-containing products eg, Berodual/F UDV 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 eg, Berodual/F UDV, 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/F UDV under medical supervision.
In the following conditions, Berodual/F UDV 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 and pheochromocytoma.
Potentially serious hypokalemia may result from β2-agonist therapy.
Berodual/F UDV should be used with caution in patients with prostatic hypertrophy 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 and corneal congestion may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.
Patients must be instructed in the correct administration of Berodual inhalation 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.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Genotoxicity and carcinogenicity studies were not conducted with Berodual/F UDV. 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 inhalative 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.
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 Berodual/F UDV 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. Although lipid-insoluble quaternary bases pass into breast milk, 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/F UDV is administered to a nursing woman.
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 Berodual/F UDV 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. Although lipid-insoluble quaternary bases pass into breast milk, 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/F UDV is administered to a nursing woman.
Frequent undesirable effects of Berodual/F UDV are fine tremor of skeletal muscles, nervousness and dryness of the mouth; less frequent are headache, dizziness, tachycardia and palpitations, especially in susceptible patients.
Potentially serious hypokalemia may result from β2-agonist therapy.
As with use of other inhalation therapy, cough, local irritation and less common, inhalation-induced bronchospasm have been reported.
As with other β-agonist-containing products, nausea, vomiting, sweating, weakness and myalgia/muscle cramps may occur. In rare cases, decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmias, particularly after higher doses, may occur.
In individual cases, psychological alterations have been reported under inhalational therapy with β-agonist-containing products.
Ocular accommodation disturbances, gastrointestinal motility disturbances and urinary retention are rare and reversible.
Ocular side effects have been reported (see Precautions).
In rare cases, skin reactions or allergic-type reactions eg, skin rash, angioedema of the tongue, lips and face, and urticaria may occur.
Other β-adrenergics and 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 side effects.
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, steroids 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.
Beta-adrenergic agonists 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.
Berodual MDI: The container is under pressure and should on no account be opened by force or exposed to temperatures exceeding 50°C. As the container is not transparent, it is not possible to see when the contents are used up, but shaking the container will show if there is any remaining fluid. 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 clear water.
Berodual F UDV: Since the UDVs contain 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.
Berodual MDI: Store below 30°C.
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.
Berodual MDI: Metered-dose inhaler 10 mL.
Berodual F UDV: Unit-dose vial 4 mL x 20's.