1. Name Of The Medicinal Product
Duovent UDVs
2. Qualitative And Quantitative Composition
Each single dose unit contains Fenoterol Hydrobromide 1.25 mg and Ipratropium Bromide 0.5 mg.
For excipients, see Section 6.1.
3. Pharmaceutical Form
Nebuliser solution.
A clear, colourless or almost colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
The management of acute severe asthma or acute exacerbation of chronic asthma presenting as an emergency requiring treatment by nebuliser.
4.2 Posology And Method Of Administration
DUOVENT UDVs may be administered from an intermittent positive pressure ventilator or from a properly maintained and functioning nebuliser.
The recommended dose for adults and children over 14 years is one vial (4 ml) to be nebulised immediately upon presentation. Each dose should be inhaled to dryness from the nebuliser. Repeat dosing may be given at the discretion of the treating physician, up to a maximum of 4 vials in 24 hours.
In acute severe asthma additional doses may be necessary depending on clinical response. Nebuliser treatment of acute severe asthma should be replaced by standard inhaler devices 24 - 48 hours before discharge unless the patient requires a nebuliser at home.
Clinical trials have included patients over 65 years. No adverse reactions specific to this age group have been reported.
Administration
DUOVENT UDVs should only be used in a nebuliser approved by your doctor.
1. The nebuliser or ventilator unit should be prepared by following the manufacturer's instructions and /or the advice of the physician.
2. A new single dose unit should be carefully separated from the strip. NEVER use one which has been previously opened.
3. Open the single dose unit by simply twisting off the top, always taking care to hold it in an upright position.
4. Unless otherwise instructed, all the contents of the single dose unit should be squeezed into the nebuliser chamber. If dilution of the single dose unit contents is necessary this should be done using ONLY sterile sodium chloride 0.9% solution as directed by the physician.
5. Use your nebuliser as directed by your doctor.
6. After nebulisation has finished, throw away any remaining solution from the single dose unit or nebuliser chamber.
7. Follow the manufacturer's instructions for cleaning the nebuliser. It is important that the nebuliser is kept clean.
4.3 Contraindications
Hypertrophic obstructive cardiomyopathy, tachyarrhythmia. Hypersensitivity to fenoterol hydrobromide or atropine-like substances or to any of the excipients of the product.
4.4 Special Warnings And Precautions For Use
Patients must be instructed in the correct use of a nebuliser and warned not to exceed the prescribed dose. The patient must be instructed to seek medical advice in the event of DUOVENT failing to provide relief of bronchospasm. In the case of acute, rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.
DUOVENT should be used only on an as-needed basis. 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 deterioration of disease control.
The use of increasing amounts of beta2-agonist containing products such as DUOVENT 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 beta2-agonist containing products such as DUOVENT, 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 DUOVENT under medical supervision.
In the following conditions DUOVENT should only be used after careful risk/benefit assessment, especially when doses higher than recommended are used:
Insufficiently controlled diabetes mellitus, myocardial insufficiency, angina, cardiac dysrhythmias, hypertension, recent myocardial infarction, hypertrophic subvalvular aortic stenosis, severe organic heart or vascular disorders, hyperthyroidism, pheochromocytoma.
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 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.
The administration of nebuliser solutions has occasionally been associated with cases of paradoxical bronchoconstriction.
Potentially serious hypokalaemia may result from beta2-agonist therapy. DUOVENT should be used with caution in patients predisposed to or with narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-neck obstruction).
Patients must be instructed in the correct administration of DUOVENT UDVs. Care should be taken to prevent the solution or mist from entering the eyes. It is recommended that the nebulised solution is administered via a mouth piece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.
There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes.
Inhaled doses of ipratropium bromide nebuliser solution up to 1 mg have not been associated with elevation of intra-ocular pressure.
Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma.
Should any combination of these symptoms develop, treatment with miotic eye drops should be initiated and specialist advice sought immediately.
As patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances, DUOVENT as with other anticholinergics should be used with caution in these patients.
Immediate hypersensitivity reactions may occur after administration of DUOVENT, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.
The use of DUOVENT may lead to positive results with regard to fenoterol in tests for nonclinical substance abuse, e.g. in the context of athletic performance enhancement (doping).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In view of a possible interaction between sympathomimetic amines and monoamine oxidase inhibitors or tricyclic antidepressants, care should be exercised if it is proposed to administer these compounds concurrently with DUOVENT UDVs.
DUOVENT UDVs should be used with caution in patients already receiving other sympathomimetic agents as cardiovascular effects may be additive.
Other beta-adrenergics and anticholinergics and xanthine derivatives (such as theophylline) may enhance the bronchodilatory effect. The concurrent administration of other beta-mimetics, systemically available anticholinergics and xanthine derivatives (e.g. theophylline) may increase the adverse reactions.
Beta-adrenergic blocking agents may antagonise fenoterol hydrobromide and potentially seriously reduce its bronchodilator effect if administered concurrently.
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 effect of hypokalemia on cardiac rhythm. It is recommended that serum potassium levels are monitored in such situations.
Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.
4.6 Pregnancy And Lactation
Although both fenoterol hydrobromide and ipratropium bromide have been in general use for several years, there is no definite evidence of ill-consequence during human pregnancy; animal studies have shown no hazard. Medicines should, however, not be used in pregnancy, especially during the first trimester, unless the expected benefit is thought to outweigh any possible risk to the foetus.
Beta-adrenergic agents have been shown to prolong pregnancy and inhibit labour. The inhibitory effect of fenoterol hydrobromide on uterine contraction should be taken into account when considering the risk:benefit balance.
Preclinical studies have shown that fenoterol hydrobromide is excreted in breast milk. It is unknown whether ipratropium is excreted into breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with DUOVENT should be made taking into account the benefit of breast-feeding to the child and the benefit of DUOVENT therapy to the mother.
4.7 Effects On Ability To Drive And Use Machines
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. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.
4.8 Undesirable Effects
Many of the listed undesirable effects can be assigned to the anticholinergic and beta-adrenergic properties of DUOVENT. As with all inhalation therapy DUOVENT 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.
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.
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4.9 Overdose
Symptoms
The effects of overdosage are expected to be primarily related to fenoterol. The expected symptoms of overdosage are those of excessive beta-adrenergic-stimulation, the most prominent being tachycardia, palpitation, hypertension, hypotension, widening of the pulse pressure, anginal pain, arrhythmias, flushing, nausea, restlessness, dizziness, headache and tremor.
Hypokalaemia may occur following overdose with fenoterol. Serum potassium levels should be monitored.
Inhaled doses of 5 mg ipratropium produce an increase in heart rate and palpitation but single doses of 2 mg have been given to adults and 1 mg to children without causing side-effects. Single doses of ipratropium bromide 30 mg by mouth cause anticholinergic side-effects but these are not severe and do not require specific reversal.
Therapy
It is suggested that the patient should be treated symptomatically. Beta1-selective beta-adrenergic blocking agents should be chosen and blood pressure should be monitored. Should the administration of a beta-adrenergic blocking agent be considered necessary to counteract the effects of overdosage, its use in a patient liable to bronchospasm should be carefully monitored because of the risk of precipitating severe bronchospasm, which may be fatal.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
DUOVENT contains two active bronchodilating ingredients: ipratropium bromide, exhibiting an anticholinergic effect and fenoterol hydrobromide a beta-adrenergic agent.
Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonising 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.
A single dose randomised double-blind cross-over controlled trial (trial number 03.53.02.) in 15 patients with bronchospasm associated with chronic bronchitis studied the combination of fenoterol 50µ and ipratropium 20µ versus the individual components and placebo. The study showed significant improvements in pulmonary function (FEV1 p<0.05 and FEF25-75% p<0.05 increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted in the majority of patients up to 6 hours
A multidose randomised double-blind cross-over trial (trial number 03.53.01) where therapy was given over periods of two weeks at a time in 17 patients with chronic bronchitis studied the combination of fenoterol 50µ and ipratropium 20µ versus the individual components and significant improvements in FEV1 p<0.0004 were observed.
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 such as increase in heart rate and contractility, are caused by the vascular effects of fenoterol, cardiac beta2-receptor stimulation, and at supratherapeutic doses, by beta1-receptor stimulation. As with other beta-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 beta-agonists. Unlike the effects on the bronchial smooth muscle, the systemic effects of ß-agonists are subject to the development of tolerance.
5.2 Pharmacokinetic Properties
About 16% of the dose is deposited in the respiratory tract following inhalation by metered aerosol. The active ingredients (fenoterol hydrobromide 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 hydrobromide
The swallowed portion is mainly metabolised to sulfate conjugates. The absolute bioavailability following oral administration is low (approx. 1.5%). Following intravenous administration, a three compartmental pharmacokinetic profile was observed, whereby the terminal half-life was approximately 3 hours. 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 non-metabolised state, fenoterol hydrobromide can slowly pass through the placenta. It is also excreted into breast milk.
Ipratropium bromide
The absolute bioavailability after oral administration is low (approx. 2%). Following intravenous administration, a rapid biphasic decline in plasma is noted for ipratropium. The terminal half-life was about 1.6 hours. 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% non-renal i.e. mainly hepato-metabolic. The main metabolites found in urine bind poorly to the muscarinic receptor. Approximately forty percent of the active ingredient is excreted renally after intravenous administration, 4.4% - 13.1% after inhalation from a metered dose inhaler is excreted as unchanged compound in urine. The drug is minimally (less than 20%) bound to plasma proteins. Ipratropium is a quaternary ammonium compound which is poorly absorbed from the gastrointestinal tract and is slow to cross mucous membranes and the blood brain barrier.
5.3 Preclinical Safety Data
None stated.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Hydrochloric acid
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
As the product contains no preservative, a fresh vial should be used for each dose and the vial should be opened immediately before administration. Any solution left in the vial should be discarded.
6.4 Special Precautions For Storage
Do not store above 25°C. Protect from heat. Keep vials in the outer carton.
6.5 Nature And Contents Of Container
Low density polyethylene (LDPE) vials formed in strips of 10 packed into cartons containing 10, 20, 30, 50, 60, 80, 100, 120, 150, 200, 500 and 1000 vials. Each vial contains 4 ml of solution.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements
7. Marketing Authorisation Holder
Boehringer Ingelheim Limited,
Ellesfield Avenue,
Bracknell,
Berkshire,
RG12 8YS,
United Kingdom.
8. Marketing Authorisation Number(S)
PL 00015/0164
9. Date Of First Authorisation/Renewal Of The Authorisation
09/06/93
10. Date Of Revision Of The Text
March 2011
11. LEGAL CATEGORY
POM
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