Atrovent (Ipratropium Bromide)

ATROVENT® Nasal Spray

Boehringer Ingelheim

Ipratropium Bromide

Topical Anticholinergic

Action And Clinical Pharmacology: Ipratropium, a quaternary ammonium derivative of atropine, is an anticholinergic drug. Ipratropium administered intranasally has a localized parasympathetic blocking action which reduces watery hypersecretion from mucosal glands in the nose.

Two nasal provocation trials in perennial rhinitis patients (n=44) using ipratropium nasal spray showed a dose-dependent increase in inhibition of methacholine-induced nasal secretion with an onset of action within 15 minutes. The duration of action of the nasal spray was also dose-dependent.

Ipratropium administration via nasal aerosol had no marked effect on sense of smell, nasal mucociliary transport, ciliary beat frequency or the air-conditioning capacity of the nose.

Ipratropium is not readily absorbed into the systemic circulation from the nasal mucosa as confirmed by blood level measurements and renal excretion studies with ipratropium nasal spray 0.03%, 0.06% and 0.12%. The plasma half-life in man is less than 2 hours after i.v. administration of ipratropium. Serum protein binding is less than 20%. In placebo-controlled pharmacokinetic trials in a total of 17 volunteers, 0.03%, 0.06%, and 0.12% concentrations of ipratropium nasal spray exhibited linear kinetics up to a total dose of 336 g. One clinical trial has shown that the rate of ipratropium absorption was accelerated in a limited number of perennial rhinitis patients (n=4) using ipratropium nasal spray 0.06% chronically versus normal patients (cross trial comparison). This is presumably due to an inflamed nasal mucosa which is, therefore, more permeable. However, the extent of absorption was the same for patients and normal volunteer groups. Since there was no increase in the frequency of systemic adverse events, the clinical significance of this increased rate of absorption is not known.

Studies in rats have shown that ipratropium does not cross the blood-brain barrier.

In double-blind, placebo-controlled, crossover, single dose pharmacokinetic trials (n=17), ipratropium nasal spray 0.03%, 0.06%, and 0.12% (84 g, 168 g and 336 g total nasal dose, respectively) did not significantly affect pupillary diameter, or have any systemic anticholinergic physiologic effect (i.e., changes in heart rate or systolic/diastolic blood pressure) or adverse events (e.g., dry mouth, blurred vision, constipation, difficulty urinating, etc.).

Indications And Clinical Uses: Nasal Spray 0.03%: For the symptomatic relief of rhinorrhea associated with allergic or nonallergic perennial rhinitis.

Nasal Spray 0.06%: For the symptomatic relief of rhinorrhea associated with the common cold.

Contra-Indications: Known hypersensitivity to ipratropium, atropinics or to any of the ingredients of the nasal spray (see Supplied).

Manufacturers’ Warnings In Clinical States: Care should be taken to ensure that the nasal spray does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle-closure glaucoma and eye pain) when aerosolized ipratropium has been released into the eyes.

Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion may be signs of acute angle-closure 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 the nasal spray. Care must be taken not to allow the aqueous spray into the eyes. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

Precautions: Caution should be taken to avoid accidental release of the nasal spray into the eyes.

Patients with or predisposed to narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction should use ipratropium nasal spray with caution.

Pregnancy: The safety of ipratropium nasal spray administration during pregnancy has not yet been established. The benefits of using ipratropium when pregnancy is confirmed or suspected must be weighed against possible hazards to the fetus. Studies in rats, mice and rabbits showed no embryotoxic effects nor teratogenic effects.

Lactation: No specific studies have been conducted on excretion of ipratropium in breast milk. Benefits of nasal spray use during lactation should therefore be weighed against possible effects on the infant.

Children: There is insufficient evidence available at present to recommend ipratropium nasal spray for use in children under 12 years of age.

Drug Interactions: If patients are receiving other anticholinergic drugs, ipratropium nasal spray should be used with caution because of possible additive effects.

Although the open-label, long-term studies to date have not shown a drug-drug interaction, ipratropium nasal spray should be used with caution in patients concomitantly using intranasal steroids because of the possible adverse local effects, (e.g., epistaxis, etc.). Any patient who experiences the above adverse effect should contact their doctor and a reduction in dose or frequency of ipratropium nasal spray or the nasal steroid should be considered.

Adverse Reactions: Nasal Spray 0.03%: Adverse reaction information concerning Atrovent nasal spray 0.03% in patients with perennial rhinitis is derived from 5 multicentre, placebo-controlled clinical trials involving 854 patients (454 patients on Atrovent and 400 patients on placebo), and a 1-year open-label, follow-up trial. In 3 of the placebo-controlled trials, patients received Atrovent nasal spray, 42 g per nostril, or placebo 3 times daily, for 8 weeks. In the other 2 placebo-controlled trials, Atrovent nasal spray, 21 or 42 g per nostril, was administered to patients 2 or 3 times daily for 4 weeks. Of the 285 patients who entered the open-label, follow-up trial, 232 were treated for 3 months, 200 for 6 months, and 159 up to 1 year, with the majority (>86%) of patients going 1 year being maintained on 42 g per nostril, 2 or 3 times daily, of Atrovent nasal spray.

Adverse events were usually mild to moderate and transient in the 5 placebo-controlled trials, resulting in discontinuation of treatment for 5.3% of the Atrovent nasal spray 0.03% and 5.3% of the placebo-treated patients. There was no evidence of nasal rebound (i.e., a clinically significant increase in rhinorrhea, posterior nasal drip, sneezing or nasal congestion severity compared to baseline) upon discontinuation of double-blind therapy in these trials. There were no drug-related serious or anticholinergic adverse events (with the exception of dry mouth reported for 1% of the Atrovent and 0.5% of the placebo-treated patients) during the placebo-controlled trials or the 1-year open-label, follow-up trial in patients on Atrovent nasal spray 0.03%.

Nasal adverse events were reported for 84 (29.5%) of the 285 patients in the 1-year open-label, follow-up trial; 16.5% of these events were considered drug-related by the physicians conducting the trial. The incidence (and assessment of drug relationship) for the most frequently reported nasal adverse events were nasal congestion 11.6% (1.4% drug-related), nasal dryness 10.2% (9.5% drug-related), and epistaxis 4.9% (4.2% drug-related). Nasal dryness and/or epistaxis occurred in 45 patients. It resolved with continued treatment or dose reduction in 40 of these patients (89%), and required discontinuation of treatment in 5 patients (11%).

Adverse events, reported as possibly related to drug treatment, which were found in less than 2% of perennial rhinitis patients receiving Atrovent nasal spray 0.03% in the 5 multicentre, placebo-controlled clinical trials and 1 year open-label follow-up trial were: paresthesia, fatigue, dizziness, insomnia, dysphonia, migraine, vertigo, rash, furunculosis, urticaria, generalized edema, diarrhea, abdominal pain, taste perversion, conjunctivitis and xerophthalmia.

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. These ocular events have not been reported with the use of Atrovent nasal spray.

Nasal Spray 0.06%: Adverse reaction information concerning Atrovent nasal spray 0.06% in patients with the common cold is derived from 2 multicentre, placebo-controlled clinical trials involving 1 276 patients (195 patients on Atrovent nasal spray 0.03%, 352 patients on Atrovent nasal spray 0.06%, 189 patients on Atrovent nasal spray 0.12%, 351 patients on placebo and 189 patients receiving no treatment).

Adverse events, reported as possibly related to drug treatment, which were found in less than 1% of patients with the common cold receiving Atrovent nasal spray 0.06% in 2 multicentre, placebo-controlled clinical trials were: paresthesia, dizziness, dysphonia, tachycardia, taste perversion, conjunctivitis and abnormal vision.

Atrovent nasal spray 0.06% was well tolerated by the patients, with the most frequently reported adverse events being minor local nasal adverse events. The majority of the adverse events were mild to moderate in nature, none were considered serious, none resulted in hospitalization and no patient receiving Atrovent nasal spray 0.06% was discontinued from the trial due to a drug-related adverse event. There was no evidence of rebound of nasal symptoms.

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. These ocular events have not been reported with the use of Atrovent nasal spray.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute overdosage by intranasal administration is unlikely since ipratropium is not well absorbed systemically after intranasal or oral administration.

Should signs of serious anticholinergic toxicity appear, cholinesterase inhibitors may be considered.

Dosage And Administration: The dose of nasal spray 0.03% for symptomatic relief of rhinorrhea associated with allergic or nonallergic perennial rhinitis is 2 sprays (42 g) per nostril 2 or 3 times a day (total dose 168 to 252 g/day). Optimum dosage varies with the response of the individual patient.

The dose of nasal spray 0.06% is 2 sprays (84 g) per nostril 3 or 4 times daily (total doses 504 to 672 g/day) as required for symptomatic relief of rhinorrhea associated with the common cold.

Treatment in the common cold has only been studied up to 4 days. Efficacy and safety of treatment beyond 4 days has not been established, although there has been no evidence of adverse safety effects with longer treatment in perennial rhinitis patients.

Children: Not recommended for use in children under 12 years of age.

Availability And Storage: 0.03%: Each spray is designed to deliver 0.07 mL which contains: ipratropium bromide 21 g. Nonmedicinal ingredients: benzalkonium chloride, edetate disodium, hydrochloric acid, sodium chloride, sodium hydroxide and purified water. Bottles of 30 mL, fitted with a metered nasal spray pump, a safety clip to prevent accidental discharge of the spray and a clear plastic dust cap. The 30 mL bottle is designed to deliver 345 sprays of 0.07 mL each or 28 days of therapy at the maximum recommended dose (2 sprays per nostril 3 times a day).

0.06%: Each spray is designed to deliver 0.07 mL which contains: ipratropium bromide 42 g. Nonmedicinal ingredients: benzalkonium chloride, edetate disodium, hydrochloric acid, sodium chloride, sodium hydroxide and purified water. Bottles of 15 mL, fitted with a metered nasal spray pump, a safety clip to prevent accidental discharge of the spray and a clear plastic dust cap. The 15 mL bottle is designed to deliver 165 sprays of 0.07 mL each or 10 days of therapy at the maximum recommended dose (2 sprays per nostril 4 times a day).

Store tightly closed between 15 and 30°C. The contents are stable up to the expiration date stamped on the label. Avoid excessive heat or freezing. Keep out of reach of children. (Shown in Product Recognition Section)

ATROVENT® Nasal Spray Boehringer Ingelheim Ipratropium Bromide Topical Anticholinergic

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