Source: Marketing Authorisation Holder Revision Year: 2015
Like other nebulizer solutions that contain β2 agonists, DUOVENT UDV (ipratropium bromide/fenoterol hydrobromide) should not be used on a regular basis without appropriate concomitant anti-inflammatory therapy (see DOSAGE AND ADMINISTRATION).
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, insufficiently controlled diabetes mellitus, or pheochromocytoma.
If therapy does not produce a significant improvement or if the patient’s condition gets worse, medical advice must be sought in order to determine a new plan of treatment. In the case of acute or rapidly worsening dyspnea, a doctor should be consulted immediately.
Increasing use of β2 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 AND ADMINISTRATION).
Concomitant use of DUOVENT UDV (ipratropium bromide/fenoterol hydrobromide) 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 (see DRUG INTERACTIONS).
The bronchodilating action of sympathomimetic drugs may be antagonized by β adrenergic blocking agents with the result that the respiratory status of patients may worsen when the two drugs are used concomitantly. In patients requiring concomitant treatment with DUOVENT UDV and a β adrenergic blocking agent, the use of a relatively cardioselective β blocker (e.g. metoprolol, atenolol, acebutolol) must be considered. During the concomitant treatment, patients should be monitored carefully for possible deterioration in pulmonary function or for the need to adjust the dosage of either drug.
Caution is advised against accidental release of the solution into the eyes.
DUOVENT UDV should be used with caution in patients predisposed to narrow-angle glaucoma or with pre-existing-urinary outflow tract obstruction (e.g. prostatic hyperplasia, or bladder neck obstruction) and in asthmatic or emphysematous patients who also have acute and recurring congestive heart failure or in patients sensitive to sympathomimetic amines.
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.
Failure to respond to a previously effective dose usually indicates a significant deterioration in the patient’s asthmatic condition. The patient should be instructed to contact his/her physician immediately in these circumstances and warned on no account to exceed the recommended dose.
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 (fenoterol hydrobromide) 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.
The use of DUOVENT UDV may lead to positive results with regards to fenoterol in tests for nonclinical substance abuse, e.g. in the context of athletic performance enhancement (doping).
Animal data only (see TOXICOLOGY).
Cardiovascular effects may be seen with sympathicomimetic drugs, including DUOVENT. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta-agonists. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving DUOVENT, should be warned to seek immediate medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.
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.
In common with other β adrenergic agents, fenoterol hydrobromide 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 β2 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 (see OVERDOSAGE).
Hypokalemia will increase the susceptibility of digitalis-treated patients to cardiac arrhythmias.
Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.
Immediate hypersensitivity reactions may occur after administration of DUOVENT, as demonstrated by rare cases of urticaria, angio-edema, bronchospasm, oropharyngeal edema and anaphylaxis.
Care should be taken to ensure that the nebulizer mask fits the patient’s face properly and that nebulizer solution does not escape into the eyes (e.g. use swimming goggles with the mask, or use a mouth piece). In patients with glaucoma or narrow anterior chambers, the administration by nebulizer of DUOVENT UDV should be avoided unless measures (e.g. use of swimming goggles or mouthpiece) are taken to ensure that nebulized solution does not reach the eye. Exposure of the eyes of such patients to a nebulized combination of ipratropium bromide and a β2 agonist solution (e.g. DUOVENT UDV) has been reported to result in increased intraocular pressure and/or acute angle closure. There have been isolated reports of ocular complications (e.g. mydriasis, increased intraocular pressure, angle closure glaucoma, eye pain) when nebulized ipratropium bromide either alone or in combination with an adrenergic β2 agonist solution has escaped into the eyes. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.
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 advice sought immediately.
Paradoxical bronchospasm: Some patients receiving inhaled β 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.
Use of DUOVENT UDV 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.
In patients with bronchial asthma DUOVENT UDV should be used only on an as-needed basis. In patients with mild COPD, on-demand (symptom-oriented) treatment may be preferable to regular use.
Clinical data on fertility are neither available for the combination of ipratropium bromide and fenoterol hydrobromide nor for each of the two components of the combination. Preclinical studies performed with the individual components ipratropium bromide and fenoterol hydrobromide showed no adverse effect on fertility (see TOXICOLOGY).
The safety of DUOVENT UDV in pregnancy and lactation has not been established. It should be used with caution before childbirth in view of the inhibiting effect of fenoterol on uterine contractions.
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.
Non-clinical studies have shown that fenoterol hydrobromide is excreted into breast milk. It is unknown whether ipratropium is excreted into breast milk. But it is unlikely that ipratropium would reach the infant to an important extent especially when administered to the mother by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when DUOVENT is administered to a nursing woman.
DUOVENT UDV is 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.
No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that they may experience undesirable effects such as dizziness, tremor, accommodation disorder, mydriasis and blurred vision during treatment with DUOVENT UDV. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.
Frequent undesirable effects of DUOVENT UDV (ipratropium bromide/fenoterol hydrobromide) are fine tremor of skeletal muscles and nervousness, less frequent are tachycardia, increased heart rate, dizziness, palpitations or headache, especially in hypersensitive patients.
Potentially serious hypokalemia may result from beta2 agonist therapy (see OVERDOSAGE).
In isolated cases there may be local reactions such as dryness of the mouth, throat irritation, pharyngitis or allergic reactions. As with use of other inhalation therapy, cough, local irritation (such as pharyngitis, throat irritation) and 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, atrial fibrillation and supraventricular tachycardia and myocardial ischaemia may occur.
In individual cases, psychological alterations have been reported under inhalational therapy with β agonist containing products.
Because of the low systemic absorption of ipratropium bromide, ocular accommodation disturbances, gastrointestinal motility disturbances (vomiting, constipation, and diarrhea) and urinary retention are rare and reversible.
Ocular side effects (including accommodation disturbances and glaucoma) may occur (see WARNINGS AND PRECAUTIONS).
Skin reactions or allergic-type reactions such as skin rash, angioedema of the tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions have been reported.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The most frequent side effects reported in clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, blood pressure systolic increased and nervousness.
The adverse reactions noted for the individual components of DUOVENT UDV nebulizer solution are as follows:
The frequency of adverse reactions recorded in 214 patients receiving Atrovent (ipratropium bromide) solution was as follows (given by adverse effect: % of patients): Dry mouth or throat (9.3); Bad taste (5.1); Tremor (4.2); Exacerbation of symptoms (4.2); Burning eyes (0.9); Nausea (0.9); Sweating (0.9); Cough (0.9); Headache (0.5); Palpitations (0.5).
The adverse effect judged to be most severe was exacerbation of symptoms. This occurred in 8 patients treated with Atrovent solution alone, 6 of whom withdrew from the clinical studies.
Bronchospasm occurred in 3 patients with acute severe asthma who received Atrovent solution alone. In two patients, this was reversed after therapy with a β2 sympathomimetic solution. The third patient received no other therapy.
The following table compares the incidence of adverse effects of the combination of Atrovent and a β2 agonist solution with that of the β2 agonist alone.
| ADVERSE EFFECT | ATROVENT - β2 AGONIST (% of 94 patients) | β2 AGONIST (% of 96 patients) |
|---|---|---|
| Tremor | 31.9 | 26.0 |
| Dry mouth | 16.0 | 28.1 |
| Bad taste | 16.0 | 13.5 |
| Vomiting | 2.1 | 2.1 |
| Palpitations | 2.1 | 1.0 |
| Headache | 1.1 | 2.1 |
| Cough | 1.1 | 0.0 |
| Flushing | 1.1 | 0.0 |
| Dizziness | 0.0 | 1.0 |
| Numbness in leg | 0.0 | 1.0 |
There have been isolated reports of ocular effects such as mydriasis, increased intraocular pressure, and acute glaucoma associated with the escape of nebulized ipratropium bromide (alone or in combination with a β2 agonist) solution into the eyes.
At the most frequently used dosage of fenoterol hydrobromide solution of 0.5 to 1.0 mg, tremor occurred in 12% of patients. At higher doses of fenoterol hydrobromide 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 hydrobromide solution, 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.
Local irritation or allergic reactions have been reported rarely. As with other bronchodilators, cough and, very rarely, paradoxical bronchospasm have been observed (see WARNINGS AND PRECAUTIONS). Potentially serious hypokalemia may result from β2 agonist therapy.
Many of the listed undesirable effects can be assigned to the anticholinergic and beta2- sympathomimetic properties of DUOVENT UDV. As with all inhalation therapy DUOVENT UDV may show symptoms of local irritation. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.
Other β adrenergic agents, anticholinergics, xanthine derivatives (such as theophylline) and corticosteroids may enhance the effect of DUOVENT UDV nebulizer solution. The concurrent administration of other beta mimetics, systemically available anticholinergics and xanthine derivatives (e.g. theophyline) may increase the adverse reactions.
A potentially serious reduction in bronchodilation may occur during concurrent administration of beta receptor blocking agents and fenoterol hydrobromide as these two agents inhibit the effects of one another (see WARNINGS AND PRECAUTIONS).
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.
Avoid concomitant use of beta2-agonist containing medicinal products with monoamine oxidase inhibitors, tricyclic antidepressants or with other sympathomimetic agents since their combined effect on the cardiovascular system may be deleterious to the patient.
Inhalation of halogenated hydrocarbon anesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility of the cardiovascular effects of beta agonists.
The chronic co-administration of DUOVENT UDV with other anticholinergic drugs has not been studied. Therefore, the chronic co-administration of DUOVENT UDV nebulizer solution with other anticholinergic drugs is not recommended.
Beta adrenergic agents have been shown to delay preterm labour in some reports. There are no well-controlled studies which demonstrate that such agents will stop preterm labour or prevent labour at term. Cautious use of β adrenergics for the relief of bronchospasm is therefore required in pregnant patients to avoid interference with uterine contractility.
The safety of DUOVENT during lactation has not been established.
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