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Ipratropium Bromide
Nasal Solution 0.03% (Nasal Spray)

Rx only

Prescribing Information

DESCRIPTION

The active ingredient in Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is ipratropium bromide monohydrate. It is an anticholinergic agent chemically described as 8-azoniabicyclo (3.2.1) octane,3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide, monohydrate (endo,syn)-, (±)- :a synthetic quaternary ammonium compound, chemically related to atropine. Its structural formula is:

Ipratropium bromide is a white to off-white, crystalline substance. It is freely soluble in lower alcohols and water, existing in an ionized state in aqueous solutions, and relatively insoluble in non-polar media.

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is a metered-dose, manual pump spray unit which delivers 21 mcg (70 µL) ipratropium bromide per spray on an anhydrous basis in an isotonic, aqueous solution with pH adjusted to 4.7. It also contains benzalkonium chloride, edetate disodium, sodium chloride, sodium hydroxide, hydrochloric acid, and purified water. Each bottle contains 345 sprays.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ipratropium bromide is an anticholinergic agent that inhibits vagally-mediated reflexes by antagonizing the action of acetylcholine at the cholinergic receptor. In humans, ipratropium bromide has anti-secretory properties and, when applied locally, inhibits secretions from the serous and seromucous glands lining the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal and gastrointestinal membrane and the blood-brain barrier, resulting in a reduction of the systemic anticholinergic effects (e.g., neurologic, ophthalmic, cardiovascular, and gastrointestinal effects) that are seen with tertiary anticholinergic amines.

Pharmacokinetics

Clinical Trials

The clinical trials for Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) were conducted in patients with nonallergic perennial rhinitis (NAPR) and in patients with allergic perennial rhinitis (APR). APR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing when exposed to specific perennial allergens (e.g., dust mites, molds) and were skin test positive to these allergens. NAPR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing throughout the year, but were skin test negative to common perennial allergens. In four controlled, four and eight week comparisons of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) (42 mcg per nostril, two or three times daily) with its vehicle, in patients with allergic or nonallergic perennial rhinitis, there was a statistically significant decrease in the severity and duration of rhinorrhea in the ipratropium bromide group throughout the entire study period. An effect was seen as early as the first day of therapy. There was no effect of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) on degree of nasal congestion, sneezing or postnasal drip. The response to Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) did not appear to be affected by the type of perennial rhinitis (NAPR or APR), age, or gender. No controlled clinical trials directly compared the efficacy of BID versus TID treatment.

INDICATIONS AND USAGE

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is indicated for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children age 6 years and older. Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) does not relieve nasal congestion, sneezing or postnasal drip associated with allergic or nonallergic perennial rhinitis.

CONTRAINDICATIONS

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients.

WARNINGS

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.

PRECAUTIONS

General

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction, particularly if they are receiving an anticholinergic by another route. Cases of precipitation or worsening of narrow-angle glaucoma and acute eye pain have been reported with direct eye contact of ipratropium bromide administered by oral inhalation.

Information for Patients

Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma or eye pain may result if Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) comes into direct contact with the eyes. Patients should be instructed to avoid spraying Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in or around their eyes. Patients who experience eye pain, blurred vision, excessive nasal dryness or episodes of nasal bleeding should be instructed to contact their doctor. Patients should be reminded to carefully read and follow the accompanying Patient's Instructions for Use.

Drug Interactions

No controlled clinical trials were conducted to investigate potential drug-drug interactions. Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is minimally absorbed into the systemic circulation; nonetheless, there is some potential for an additive interaction with other concomitantly administered anticholinergic medications, including ipratropium bromide for oral inhalation.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In two-year carcinogenicity studies in rats and mice, ipratropium bromide at oral doses up to 6 mg/kg (approximately 190 and 95 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 110 and 60 times the maximum recommended daily intranasal dose in children, respectively, on a mg/m2 basis) showed no carcinogenic activity. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test, and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Fertility of male or female rats was unaffected by ipratropium bromide at oral doses up to 50 mg/kg (approximately 1,600 times the maximum recommended daily intranasal dose in adults on a mg/m2 basis). At an oral dose of 500 mg/kg (approximately 16,000 times the maximum recommended daily intranasal dose in adults on a mg/m2 basis), ipratropium bromide produced a decrease in the conception rate.

Pregnancy

TERATOGENIC EFFECTS

Nursing Mothers

It is known that some ipratropium bromide is systemically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Although lipid-insoluble quaternary bases pass into breast milk, the minimal systemic absorption makes it unlikely that ipratropium bromide would reach the infant in an amount sufficient to cause a clinical effect. However, because many drugs are excreted in human milk, caution should be exercised when Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is administered to a nursing woman.

Pediatric Use

The safety of Ipratropium Bromide Nasal Solution (Nasal Spray) 0.03% at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6-12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of Ipratropium Bromide Nasal Solution (Nasal Spray) 0.03% for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Ipratropium Bromide Nasal Solution (Nasal Spray) 0.03% in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of the adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Ipratropium Bromide Nasal Solution (Nasal Spray) 0.03% in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Ipratropium Bromide Nasal Solution (Nasal Spray) 0.03% in patients under 6 years of age have not been established.

ADVERSE REACTIONS

Adverse reaction information on Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in patients with perennial rhinitis was derived from four multicenter, vehicle-controlled clinical trials involving 703 patients (356 patients on ipratropium bromide and 347 patients on vehicle), and a one-year, open-label, follow-up trial. In three of the trials, patients received Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) three times daily, for eight weeks. In the other trial, Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) was given to patients two times daily for four 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 one year. The majority (>86%) of patients treated for one year were maintained on 42 mcg per nostril, two or three times daily, of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray).

The following table shows adverse events, and the frequency that these adverse events led to the discontinuation of treatment, reported for patients who received Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) at the recommended dose of 42 mcg per nostril, or vehicle two or three times daily for four or eight weeks. Only adverse events reported with an incidence of at least 2.0% in the ipratropium bromide group and higher in the ipratropium bromide group than in the vehicle group are shown.

% of Patients Reporting EventsThis table includes adverse events which occurred at an incidence rate of at least 2.0% in the ipratropium bromide group and more frequently in the ipratropium bromide group than in the vehicle group.
Ipratropium Bromide
Nasal Spray 0.03%
(N=356)
Vehicle
Control
(N=347)
Incidence%Discontinued%Incidence%Discontinued%
Headache9.80.69.20
Upper respiratory tract infection9.81.47.21.4
EpistaxisEpistaxis reported by 7.0% of ipratropium bromide patients and 2.3% of vehicle patients, blood tinged nasal mucus by 2.0% of ipratropium bromide patients and 2.3% of vehicle patients.9.00.34.60.3
RhinitisAll events are uled by their WHO term; rhinitis has been presented by descriptive terms for clarification.
  Nasal dryness5.100.90.3
  Nasal irritationNasal irritation includes reports of nasal itching, nasal burning, nasal irritation and ulcerative rhinitis.2.001.70.6
  Other nasal symptomsOther nasal symptoms include reports of nasal congestion, increased rhinorrhea, increased rhinitis, posterior nasal drip, sneezing, nasal polyps and nasal edema.3.11.11.70.3
Pharyngitis8.10.34.60
Nausea2.20.30.90

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) was well tolerated by most patients. The most frequently reported nasal adverse events were transient episodes of nasal dryness or epistaxis. These adverse events were mild or moderate in nature, none was considered serious, none resulted in hospitalization and most resolved spontaneously or following a dose reduction. Treatment for nasal dryness and epistaxis was required infrequently (2% or less) and consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly or saline nasal spray). Patient discontinuation for epistaxis or nasal dryness was infrequent in both the controlled (0.3% or less) and one-year, open-label (2% or less) trials. 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.

Adverse events reported by less than 2% of the patients receiving Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) during the controlled clinical trials or during the open-label follow-up trial, which are potentially related to ipratropium bromide's local effects or systemic anticholinergic effects include: dry mouth/throat, dizziness, ocular irritation, blurred vision, conjunctivitis, hoarseness, cough and taste perversion. Additional anticholinergic effects noted with other ipratropium bromide dosage forms (ipratropium bromide inhalation solution, ipratropium bromide inhalation aerosol and Ipratropium Bromide Nasal Spray 0.06%) include: precipitation or worsening of narrow angle glaucoma, urinary retention, prostatic disorders, tachycardia, constipation, and bowel obstruction.

There were infrequent reports of skin rash in both the controlled and uncontrolled clinical studies. Other allergic-type reactions such as angioedema of the throat, tongue, lips and face, urticaria, laryngospasm and anaphylactic reactions have been reported with other ipratropium bromide products.

No controlled trial was conducted to address the relative incidence of adverse events of BID versus TID therapy.

OVERDOSAGE

Acute overdosage by intranasal administration is unlikely since ipratropium bromide is not well absorbed systemically after intranasal or oral administration. Following administration of a 20 mg oral dose (equivalent to ingesting more than four bottles of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray)) to 10 male volunteers, no change in heart rate or blood pressure was noted. Following a 2 mg intravenous infusion over 15 minutes to the same 10 male volunteers, plasma ipratropium concentrations of 22-45 ng/mL were observed (>100 times the concentrations observed following intranasal administration). Following intravenous infusion these 10 volunteers had a mean increase of heart rate of 50 bpm and less than 20 mmHg change in systolic or diastolic blood pressure at the time of peak ipratropium levels.

Oral median lethal doses of ipratropium bromide were greater than 1,000 mg/kg in mice (approximately 16,000 times the maximum recommended daily intranasal dose in adults and children on a mg/m2 basis), 1,700 mg/kg in rats (approximately 55,000 the maximum recommended daily intranasal dose in adults and children on a mg/m2 basis), and 400 mg/kg in dogs (approximately 43,000 times the maximum recommended daily intranasal dose in adults and children on a mg/m2 basis).

DOSAGE AND ADMINISTRATION

The recommended dose of Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) for the symptomatic relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis in adults and children age 6 years and older. Optimum dosage varies with the response of the individual patient.

Initial pump priming requires seven sprays of the pump. If used regularly as recommended, no further priming is required. If not used for more than 24 hours, the pump will require two sprays, or if not used for more than seven days, the pump will require seven sprays to reprime.

HOW SUPPLIED

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is supplied in a white high density polyethylene (HDPE) bottle fitted with a white and clear metered nasal spray pump, a green safety clip to prevent accidental discharge of the spray, and a clear plastic dust cap. It contains 31.1g of product formulation, 345 sprays, each delivering 21 mcg (70 µL) of ipratropium per spray, or 28 days of therapy at the maximum recommended dose (two sprays per nostril three times a day).

1 bottle per carton                NDC 49502-785-30.

Store between 15°C to 30°C (59°F to 86°F). Avoid freezing. Keep out of reach of children.

Do not spray in the eyes.

Patients should be reminded to read and follow the accompanying Patient's Instructions for Use, which should be dispensed with the product.

Rx only.

DEY
Napa, CA 94558

03-560-03

Printed: April 2003

Ipratropium Bromide
Nasal Solution 0.03% (Nasal Spray)

Patient's Instructions for Use

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is indicated for the symptomatic relief of rhinorrhea (runny nose) associated with allergic and nonallergic perennial rhinitis for adults and children age 6 years and older. Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) does not relieve nasal congestion, sneezing or postnasal drip associated with allergic or nonallergic perennial rhinitis. Read complete instructions carefully and use only as directed.

To Use:

  • Remove the clear plastic dust cap and the green safety clip from the nasal spray pump (Figure 1). The safety clip prevents the accidental discharge of the spray in your pocket or purse.
  • The nasal spray pump must be primed before Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is used for the first time. To prime the pump, hold the bottle with your thumb at the base and your index and middle fingers on the white shoulder area. Make sure the bottle points upright and away from your eyes. Press your thumb firmly and quickly against the bottle seven times (Figure 2). The pump is now primed and can be used. Your pump should not have to be reprimed unless you have not used the medication for more than 24 hours; repriming the pump will only require two sprays. If you have not used your nasal spray for more than seven days, repriming the pump will require seven sprays.
  • Before using Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray), blow your nose gently to clear your nostrils if necessary.
  • Close one nostril by gently placing your finger against the side of your nose, tilt your head slightly forward and, keeping the bottle upright, insert the nasal tip into the other nostril (Figure 3). Point the tip toward the back and outer side of the nose.
  • Press firmly and quickly upwards with the thumb at the base while holding the white shoulder portion of the pump between your index and middle fingers. Following each spray, sniff deeply and breathe out through your mouth.
  • After spraying the nostril and removing the unit, tilt your head backwards for a few seconds to let the spray spread over the back of the nose.
  • Repeat steps 4 through 6 in the same nostril.
  • Repeat steps 4 through 7 in the other nostril (i.e., two sprays per nostril).
  • Replace the clear plastic dust cap and safety clip.
  • At some time before the medication is completely used up, you should consult your physician or pharmacist to determine whether a refill is needed. You should not take extra doses or stop using Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) without consulting your physician.

To Clean:

If the nasal tip becomes clogged, remove the clear plastic dust cap and safety clip. Hold the nasal tip under running, warm tap water (Figure 4) for about a minute. Dry the nasal tip, reprime the nasal spray pump (step 2 above), and replace the plastic dust cap and safety clip.

Caution:
Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) is intended to relieve your rhinorrhea (runny nose) with regular use. It is therefore important that you use Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) as prescribed by your physician. For most patients, some improvement in runny nose is usually apparent following the first full day of treatment with Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray). Some patients may require up to two weeks of treatment to obtain maximum benefit.

Do not spray Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in your eyes. Should this occur, immediately flush your eye with cool tap water for several minutes. If you accidentally spray Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) in your eyes, you may experience a temporary blurring of vision and increased sensitivity to light, which may last a few hours. Should eye pain or blurred vision occur, contact your doctor.

Should you experience excessive nasal dryness or episodes of nasal bleeding contact your doctor.

You should not use this drug if you have glaucoma or difficult urination due to an enlargement of the prostate, unless directed by a physician.

Ipratropium Bromide Nasal Solution 0.03% (Nasal Spray) should not be used during pregnancy or breast feeding unless directed by a physician. It is not known whether ipratropium bromide is excreted in human milk; however, many drugs are excreted in human milk.

Storage:
Store between 15°C to 30°C (59°F to 86°F). Avoid freezing. Keep out of reach of children.

Manufactured by
Dey
Napa, CA 94558

03-560-03

April 2003

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