ATROVENT® Inhalation Aerosol
Action And Clinical Pharmacology: Ipratropium, a quaternary ammonium derivative of atropine is an anticholinergic drug having bronchodilator properties. On inhalation the onset of action is noted within 5 to 15 minutes with a peak response between 1 and 2 hours, lasting about 2 additional hours with subsequent decline. An inhaled dose of 40 g induces bronchodilator effect lasting for some 6 hours.
In maintenance therapy of chronic reversible airways obstruction ipratropium has been shown to provide additive bronchodilating effects to theophylline and b-adrenoceptor agonists (sympathomimetic amines). Repeated inhalation of ipratropium has not been linked to tolerance towards bronchodilating effects. Significant alterations in mucociliary clearance of sputum were not observed in short term clinical trials. Systemic absorption is poor and the blood levels reached are very low. Metabolic studies in healthy volunteers show an average elimination half-life of 3.5 hours (range 1.5 to 4 hours), the drug is transformed to some 8 metabolites with little or no anticholinergic activity.
Pharmacokinetics: In man, inhalation of 555 g of radiolabeled ipratropium bromide, about 14 times the recommended therapeutic dose, produced peak plasma levels of 0.06 ng/mL after 3 hours. The plasma concentration-versus-time curve was similar to that seen after oral administration, likely reflecting the large fraction of inhaled dose which is deposited on the pharyngeal mucosae and swallowed. I.V. administration of 1 mg in man showed a rapid distribution into tissues (half-life of a phase approximately 5 minutes), and a terminal half-life (b phase) of 3 to 4 hours. Plasma concentrations after inhaled ipratropium were about 1 000 times lower than equipotent oral or i.v. doses (15 and 0.15 mg, respectively).
Up to 8 metabolites of ipratropium have been detected in man, rat and dog. In man, about 70% of the drug is excreted unchanged after i.v. administration and only 1 metabolite exceeds 10% of the total radioactivity. The elimination occurs primarily via the kidney with less than 10% of the total i.v. dose excreted via the biliary or fecal route. After oral or inhaled doses, however, up to 90% of the dose is detectable in the feces, suggesting poor absorption.
A wide variety of challenge studies have been conducted utilizing ipratropium as a protective agent. In pharmacologically induced bronchospasm, ipratropium, in clinical doses, was very effective against methacholine and acetylcholine, moderately effective against propranolol but had little or no effect against histamine or serotonin. Studies in exercise induced bronchospasm have yielded variable results. Some investigations have indicated that the drug has little or no effect but other studies have shown that some patients, at least, are protected against bronchospasm induced by exercise. Likewise, the protective effects against cold air induced bronchospasm have been variable.
Antigen challenge studies have demonstrated that ipratropium offers some protection against the early allergic asthma response, but has no effect on the late response.
Indications And Clinical Uses: For the maintenance therapy of responsive cases of chronic reversible airways obstruction, such as chronic bronchitis and asthma.
Contra-Indications: In patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. It should also not be taken by patients hypersensitive to ipratropium bromide, atropinics or any other aerosol components.
Manufacturers’ Warnings In Clinical States: Ipratropium should not be used for the abatement of the acute asthmatic attack, since the drug has a slower onset of effect than that of an adrenergic b2 agonist aerosol.
Care should be taken to ensure that ipratropium does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, glaucoma and eye pain) when aerosolized ipratropium has been released into the eyes. Ocular events have occurred when the aerosol was used with the standard mouthpiece or with a spacing device. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.
Precautions: General: To ensure optimal delivery to the bronchial tree, the patient should be properly instructed by the physician or other health professional in the use of the inhaler.
Caution is advised against the release of the aerosol into the eyes. Due care should be taken when a spacing device is employed.
In patients with glaucoma, prostatic hypertrophy or urinary retention ipratropium should be used with caution.
If a reduced response to ipratropium becomes apparent, the patient should seek medical advice.
Like other pressurized aerosol formulations, Atrovent contains fluorocarbon propellants trichloromonofluoromethane, dichlorodifluoromethane, 1,2- dichlorotetrafluoroethane. Such propellants may be hazardous if they are deliberately abused. Inhalation of high concentrations of aerosol sprays has brought about toxic cardiovascular effects and even death, especially under conditions of hypoxia. However, evidence attests to the relative safety of aerosols when used properly and with adequate ventilation. The recommended dose should not be exceeded and the patient should be so informed.
Pregnancy: The safety in pregnancy has not been established. The benefits of using ipratropium when pregnancy is present or suspected must be weighed against the possible hazards caused to the fetus. Studies in rats, mice and rabbits showed no embryotoxic nor teratogenic effects.
Lactation: No specific studies have been conducted on excretion of this drug in breast milk. Benefits during lactation should therefore be weighed against possible effects on the infant.
Children: Efficacy and safety in children younger than 12 years has not been established.
Drug Interactions: In patients receiving other anticholinergic drugs, ipratropium should be used with caution because of possible additive effects.
Xanthine derivatives and b2 adrenergic agents may enhance the effect of ipratropium.
Adverse Reactions: The frequency of side effects reported after repeated dosing in 605 patients: dry mouth or throat (9.4%), headache (7.9%), bad taste (3.8%), blurred vision (3.1%), tremor (2.8%), palpitations (2.1%), urinary hesitation or retention (1.5%), dizziness (1.5%), stuffy nose (1.2%), difficulty in expectoration (0.7%), dyspnea (0.7%), nausea (0.5%).
There have been isolated reports of ocular events such as mydriasis, increased intraocular pressure, glaucoma and eye pain associated with the release of aerosolized ipratropium into the eyes.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Doses of ipratropium up to 1.2 mg (60 puffs) have been administered by inhalation without the appearance of serious systemic anticholinergic effects.
Should signs of serious anticholinergic toxicity appear, cholinesterase inhibitors may be considered.
Dosage And Administration: The optimal maintenance dosage must be individually determined. The recommended dosage is 2 metered doses (actuations) (40 g) 3 or 4 times daily. Some patients may need up to 4 metered doses (actuations) (80 g) at a time to obtain maximum benefit during early treatment. The maximum daily dose should not exceed 8 metered doses (actuations) (160 g) and the minimum interval between doses should not be less than 4 hours.
Stability and Storage: The aerosol canister should be stored at room temperature (15 to 30°C); the contents are stable up to the expiration date stamped on the label. Caution: contents under pressure. Container may explode if heated. Do not place in hot water or near radiators, stoves or other sources of heat. Do not puncture or incinerate container or store at temperatures over 30°C. Keep out of reach of children.
Availability And Storage: Each 10 mL metal canister with mouthpiece (oral adaptor) contains: ipratropium bromide 140 or 200 doses. Each valve depression delivers 20 g. Nonmedicinal ingredients: propellants (difluorodichloromethane, monofluorotrichloromethane, tetrafluorodichloroethane) and soya lecithin. Store between 15 and 30°C. (Shown in Product Recognition Section)
ATROVENT® Inhalation Aerosol Boehringer Ingelheim Ipratropium Bromide Bronchodilator