Ipratropium bromide anhydrous, salbutamol (as sulphate).
Metered dose inhaler: 1 metered dose contains: ipratropium bromide monohydrate 21 micrograms corresponding to 20 micrograms ipratropium bromide anhydrous; salbutamol sulphate 120 micrograms corresponding to 100 micrograms salbutamol base.
Unit dose vials: 1 unit-dose vial (2.5 ml) solution for inhalation contains: ipratropium bromide 0.52 mg corresponding to 0.5 mg ipratropium bromide anhydrous; salbutamol sulphate 3.01 mg corresponding to 2.5 mg salbutamol base.
Pharmacology: Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit 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 local and site specific to the lung and not systemic in nature.
Salbutamol sulphate is a beta2-adrenergic agent which acts on airway smooth muscle resulting in relaxation. Salbutamol relaxes all smooth muscle from the trachea to the terminal bronchioles and protects against all bronchoconstrictor challenges.
COMBIVENT provides the simultaneous release of ipratropium bromide and salbutamol sulphate allowing the additive effect on both muscarinic and beta2-adrenergic receptors in the lung resulting in a bronchodilation which is superior to that provided by each single agent.
Controlled studies in patients with reversible bronchospasm have demonstrated that COMBIVENT has a greater bronchodilator effect than either of its components and there was no potentiation of adverse events.
Pharmacokinetics: Ipratropium bromide is quickly absorbed after oral inhalation. The systemic bioavailability after inhalation is estimated to be less than 10% of the dose. Renal excretion of ipratropium bromide is given as 46% of the dose after intravenous administration. The half-life of the terminal elimination phase is about 1.6 hours as determined after intravenous administration.
The half-life for elimination of drug and metabolites is 3.6 hours, as determined after radio labeling. Ipratropium bromide does not penetrate the blood brain barrier.
Salbutamol sulphate is rapidly and completely absorbed following oral administration either by the inhaled or gastric route. Peak plasma salbutamol concentrations are seen within three hours of administration and is excreted unchanged in the urine after 24 hours. The elimination half-life is 4 hours. Salbutamol will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations.
It has been shown that co-nebulisation of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component and that therefore the additive activity of COMBIVENT is due to the combined local effect on the lung following inhalation.
COMBIVENT is indicated for the management of reversible bronchospasm associated with obstructive airway diseases in patients who require more than a single bronchodilator.
Metered dose inhaler: Adults (including elderly patients): Two inhalations four times a day.
The dose may be increased as required up to a limit of 12 inhalations in 24 hours.
Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea (difficulty in breathing) if additional inhalations do not produce an adequate improvement.
Administration: The correct operation of the metered aerosol apparatus is essential for successful therapy.
Shake the aerosol canister and depress the valve two times before the apparatus is initially used.
Before each use the following rules should be observed: 1. Remove protective cap.
2. Shake the metered aerosol well before each use.
3. Breathe out deeply.
4. Hold the metered aerosol, and close lips over the mouthpiece. The arrow and the base of the container should be pointing upwards.
5. Breathe in as deeply as possible, pressing the base of the container firmly at the same time, this releases one 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 second inhalation.
6. Replace the protective cap after use.
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.
Unit dose vials: COMBIVENT inhalation solution in unit dose vials may be administered from a suitable nebuliser or an intermittent positive pressure ventilator.
The following dose is recommended for adults (including elderly patients) and adolescents over 12 years of age.
Treatment of acute attacks: 1 unit dose vial is sufficient for prompt symptom relief in many cases.
In severe cases, if an attack has not been relieved by one unit dose vial, two unit dose vials may be required. In these cases, patients should consult the doctor or the nearest hospital immediately.
Maintenance treatment: 1 unit dose vial three or four times daily.
Instructions for use: The unit dose vials are intended only for inhalation with suitable nebulising devices and should not be taken orally or administered parenterally.
1. Prepare the nebuliser for filling, according to the instructions provided by the manufacturer or doctor.
2. Tear one unit dose vial from the strip.
3. Open the unit dose vial by firmly twisting the top.
4. Squeeze the content of the unit dose vial into the nebuliser reservoir.
5. Assemble the nebuliser and use as directed.
6. After use throw away any solution left in the reservoir and clean the nebuliser, following the manufacturer's instructions.
Since the unit dose vials 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.
It is strongly recommended not to mix COMBIVENT solution for inhalation with other drugs in the same nebuliser.
Symptoms: The effects of overdosage are expected to be primarily related to salbutamol.
The expected symptoms with overdosage are those of excessive beta-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 (such as dry mouth, visual accommodation disturbances) are mild and transient in nature in view of the wide therapeutic range and topical administration.
Therapy: Administration of sedatives, tranquillizers, in severe cases intensive therapy.
Beta-receptor blockers, preferably beta1-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.
COMBIVENT is contraindicated in patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmia.
COMBIVENT should also not be taken by patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.
COMBIVENT metered aerosol is also contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. For such patients COMBIVENT unit dose vials without soya lecithin can be used.
Immediate hypersensitivity reactions may occur after administration of COMBIVENT, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal oedema.
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 escaped into the eyes.
Eye pain or discomfort, blurred vision, visual halos or colored 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 drops should be initiated and specialist advice sought immediately.
Patients must be instructed in the correct administration of COMBIVENT.
Care must be taken not to expose the eyes to the aerosol or solution of COMBIVENT.
Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.
In the following conditions COMBIVENT 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, phaeochromocytoma, risk of narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction.
There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischaemic heart disease, tachyarrhythmia or severe heart failure) who are receiving salbutamol for respiratory disease, should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.
Potentially serious hypokalaemia may result from beta2-agonist therapy. Additionally, hypoxia may aggravate the effects of hypokalaemia on cardiac rhythm.
Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.
In the case of acute, rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.
If higher than recommended doses of COMBIVENT are required to control symptoms, the patient's therapy plan should be reviewed by a doctor.
Unit dose vials: It is recommended that the nebulised solution be administered via a mouth piece. If this is not available and a nebuliser mask is used, it must fit properly.
The safety of COMBIVENT during human pregnancy is not established. The usual precautions regarding the use of drugs in pregnancy, especially during the first trimester, should be observed. The inhibitory effect of COMBIVENT on uterine contraction should be taken into account.
Salbutamol sulphate and ipratropium bromide are probably excreted in breast milk and their effects on the neonate are not known. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when COMBIVENT is administered to a nursing woman.
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The concurrent administration of xanthine derivatives as well as other beta-adrenergics and anticholinergics may increase the side effects.
Beta-agonist induced hypokalaemia may be increased by concomitant treatment with xanthine derivatives, glucocorticosteroids and diuretics. This should be taken into account particularly in patients with severe airway obstruction.
Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving digoxin.
It is recommended that serum potassium levels are monitored in such situations.
A potentially serious reduction in bronchodilator effect may occur during concurrent administration of beta-blockers.
Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta-adrenergic agonists may be enhanced.
Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.
R03AL02 - salbutamol 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.
Unit dose vial soln for inhalation 2.5 mL x 20's.