Combivent UDV

Combivent UDV

ipratropium bromide + salbutamol

Manufacturer:

Boehringer Ingelheim

Distributor:

Metro Drug
Full Prescribing Info
Contents
Ipratropium bromide anhydrous, salbutamol sulfate.
Description
Each unit-dose vial (2.5 mL) solution for inhalation contains ipratropium bromide monohydrate 520 mcg corresponding to anhydrous ipratropium bromide 500 mcg and salbutamol sulfate 3.01 mg corresponding to 2.5 mg salbutamol base.
Ipratropium bromide is (8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate while salbutamol sulfate is di[(RS)-2-tert-butylamino-1-(4-hydroxy-3-hydroxymethyl-phenyl)ethanol] sulfate.
Action
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 sulfate is a β2-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 UDV provides the simultaneous release of ipratropium bromide and salbutamol sulfate allowing the additive effect on both muscarinic and β2-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 UDV 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 <10% of the dose. Renal excretion of ipratropium bromide is given as 46% of the dose after IV administration. The half-life (t½) of the terminal elimination phase is about 1.6 hrs as determined after IV administration.
The t½ for elimination of drug and metabolites is 3.6 hrs, as determined after radiolabeling. Ipratropium bromide does not penetrate the blood-brain barrier.
Salbutamol sulfate is rapidly and completely absorbed following oral administration either by the inhaled or gastric route. Peak plasma salbutamol concentrations are seen within 3 hrs of administration and is excreted unchanged in the urine after 24 hrs. The elimination t½ is 4 hrs.
Salbutamol will cross the blood-brain barrier reaching concentrations amounting to about 5% of the plasma concentrations.
It has been shown that co-nebulization of ipratropium bromide and salbutamol sulfate does not potentiate the systemic absorption of either component and that therefore, the additive activity of Combivent UDV is due to the combined local effect on the lung following inhalation.
Toxicology: The acute toxicity of Combivent UDV after single inhalation administration was tested in rats and dogs. Up to the highest technically testable dose (rat: 887/5397 mcg/kg body weight [ipratropium bromide/salbutamol], dog: 165/862 mcg/kg body weight [ipratropium bromide/salbutamol]), there were no indications of systemic toxic effects, the compound was locally well tolerated. The approximate LD50 after IV administration was calculated for the single substances to be between 12 and 20 mg/kg body weight for ipratropium bromide and between 60 and 70 mg/kg for salbutamol depending on the tested species ipratropium bromide (mouse, rat, dog).
Two 13-week inhalation toxicity studies in rats and dogs, respectively, have been performed with the combination of ipratropium bromide and salbutamol. In these studies, the heart proved to be the target organ. At doses of 31.3/183.4 to 375.5/2188.4 mcg/kg body weight/day ipratropium bromide/salbutamol in the rat, a non-dose-dependent increase in heart weights was observed, however without any histopathological detectable changes. In the dog at doses of 32.3/197.6 to 129.2/790.4 mcg/kg body weight/day ipratropium bromide/salbutamol, slightly increased heart rates and, at the higher dosages, histopathologically detectable scars and/or fibrosis in the papillary muscle of the left ventricle, sometimes accompanied with mineralization, were observed.
The findings obtained in the previously mentioned studies must be regarded as well-known effects of β-adrenergics as salbutamol.
The toxicological profile of the 2nd component (ipratropium bromide) is also well-known for many years and is characterized by typical anticholinergic effects as dryness of the mucosal membranes of the head, mydriasis, keratoconjunctivitis sicca (dry eye) in dogs only, reduction in tone and inhibition of motility in the gastrointestinal tract (rat).
Reproduction toxicity studies are available for the 2 individual components of Combivent UDV.
Salbutamol caused cleft palates at high doses in mice. This phenomenon is well-known and also occurs after the administration of other β-adrenergic compounds. Today, it is assumed that this effect is caused by an increase in the maternal corticosterone level and might be regarded as a result of general stress not relevant for other species. Additionally, the preclinical findings which gave rise to the suspicion that salbutamol could have teratogenic properties have already been taken into account by the restriction concerning the use in women. Apart from these findings, the studies performed with salbutamol and with ipratropium bromide revealed only marginal effects, if any, on embryos, fetuses and pups, and these are only in the range of maternal toxicity.
Both individual substances were tested in numerous in vivo and in vitro tests. Neither salbutamol nor ipratropium bromide showed any evidence of mutagenic properties.
Salbutamol and ipratropium bromide were tested separately for neoplastic properties in several in vivo carcinogenicity studies.
After oral administration of salbutamol in mice, but not in rats and dogs, an increased incidence of leiomyomas of the mesovarium was observed at doses >100 times higher than the human inhalation dose. The development of the leiomyomas was found to be preventable by simultaneous administration of β-blockers. These findings were assessed to be species-specific and without clinical relevance, consequently not leading to any restriction of the clinical use of salbutamol.
Ipratropium bromide revealed no carcinogenic potential when tested orally in mice and rats.
No evidence was found of any immunotoxicological effect caused by Combivent UDV or its single active ingredients.
Indications/Uses
Management of reversible bronchospasm associated with obstructive airway diseases.
Dosage/Direction for Use
Combivent UDV inhalation solution in unit-dose vials may be administered from a suitable nebulizer or an intermittent positive pressure ventilator.
Each unit dose vial of Combivent UDV contains 2500 mcg of salbutamol base (with each drop containing 50 mcg).
Adults and Children >12 years: 1 unit-dose vial every 6-8 hrs.
Children 2-12 years: 3 drops/kg/dose (maximum dose of 2500 mcg salbutamol) every 6-8 hrs.
Administration: The unit-dose vials are intended only for inhalation with suitable nebulizing devices and should not be taken orally.
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.
It is strongly recommended not to mix Combivent UDV solution for inhalation with other drugs in the same nebulizer.
Overdosage
Symptoms: The effects of overdosage are expected to be primarily related to salbutamol.
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, tranquillizers, in severe cases intensive therapy.
Beta-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.
Contraindications
Hypersensitivity to atropine, its derivatives or to any other component of Combivent UDV.
Patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmia.
Special Precautions
Immediate hypersensitivity reactions may occur after administration of Combivent UDV, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.
Ocular Complications: 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, 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 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.
Patients must be instructed in the correct administration of Combivent UDV. Care must be taken not to expose the eyes to the aerosol or solution of Combivent UDV.
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.
In the following conditions, Combivent 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, pheochromocytoma, risk of narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction.
Potentially serious hypokalemia may result from β2-agonist therapy. Additionally, hypoxia may aggravate the effects of hypokalemia on cardiac rhythm.
Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.
In the case of acute, rapidly worsening dyspnea (difficulty in breathing), a doctor should be consulted immediately.
If higher than recommended doses of Combivent UDV are required to control symptoms, the patient's therapy plan should be reviewed by a doctor.
Use in pregnancy & lactation: The safety of Combivent UDV during human pregnancy is not established. The usual precautions regarding the use of drugs in pregnancy, especially during the 1st trimester, should be observed.
The inhibitory effect of Combivent UDV on uterine contraction should be taken into account.
Salbutamol sulfate 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 UDV is administered to a nursing woman.
Use In Pregnancy & Lactation
The safety of Combivent UDV during human pregnancy is not established. The usual precautions regarding the use of drugs in pregnancy, especially during the 1st trimester, should be observed.
The inhibitory effect of Combivent UDV on uterine contraction should be taken into account.
Salbutamol sulfate 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 UDV is administered to a nursing woman.
Side Effects
In common with other β-agonist-containing products, more frequent undesirable effects of Combivent UDV are headache, dizziness, nervousness, tachycardia, fine tremor of skeletal muscles 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 can occur.
As with other β-mimetics, 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-mimetics.
The most frequently non-respiratory anticholinergic-related adverse events were dryness of the mouth and dysphonia.
There have been isolated reports of ocular complications (ie, mydriasis, increased intraocular pressure, angle-closure glaucoma, eye pain) when aerosolized ipratropium bromide, either alone or in combination with an adrenergic β2-agonist, has escaped into the eyes.
Ocular side effects, gastrointestinal motility disturbances and urinary retention may occur in rare cases and are reversible (see Precautions).
Allergic-type reactions eg, skin rash, angioedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported, with positive rechallenge in some cases.
Drug Interactions
The concurrent administration of xanthine derivatives as well as other β-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 β-blockers.
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 anaesthetics eg, halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of β-agonists.
Caution For Usage
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.
Storage
Store below 30°C.
ATC Classification
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.
Presentation/Packing
Inhalation soln (unit-dose vial) 2.5 mL x 20's.
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