Ipratropium Bromide Solution
FDA Label NDC 65862-905

The active ingredient in Ipratropium Bromide Inhalation Solution is ipratropium bromide monohydrate, USP. It is an anticholinergic bronchodilator 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.

Ipratropium Bromide Monohydrate Chemical Structure (Ipratropium Str)

Ipratropium bromide USP is a white to off-white crystalline powder, soluble in water, freely soluble in methanol and slightly soluble in ethanol. It is a quaternary ammonium compound and thus exists in an ionized state in aqueous solutions. It is insoluble in isopropyl alcohol, chloroform, methylene chloride and benzene.

Ipratropium Bromide Inhalation Solution is administered by oral inhalation with the aid of a nebulizer. Each mL contains ipratropium bromide, USP 0.02% (anhydrous basis) in a sterile, preservative-free, isotonic saline solution, pH adjusted to 3.4 (3 to 4) with hydrochloric acid.

Ipratropium Bromide Inhalation Solution is an anticholinergic (parasympatholytic) agent that, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve.

Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.

The bronchodilation following inhalation of Ipratropium Bromide Inhalation Solution is primarily a local, site-specific effect, not a systemic one. Much of an administered dose is swallowed but not absorbed as shown by fecal excretion studies. Following nebulization of a 2 mg dose, a mean 7% of the dose was absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide is minimally (0 to 9% in vitro) bound to plasma albumin and α₁-acid glycoproteins. It is partially metabolized. Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. Ipratropium Bromide Inhalation Solution has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

In controlled twelve-week studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV₁ increases of 15% or more) occurred within 15 to 30 minutes, reached a peak in 1 to 2 hours and persisted for periods of 4 to 5 hours in the majority of patients, with about 25 to 38% of the patients demonstrating increases of 15% or more for at least 7 to 8 hours. Continued effectiveness of ipratropium bromide was demonstrated throughout the 12-week period. In addition, significant increases in forced vital capacity (FVC) have been demonstrated. However, ipratropium bromide did not consistently produce significant improvement in subjective symptom scores nor in quality of life scores over the 12-week duration of study.

Additional controlled 12-week studies were conducted to evaluate the safety and effectiveness of Ipratropium Bromide Inhalation Solution administered concomitantly with the beta adrenergic bronchodilator solutions metaproterenol and albuterol compared with the administration of each of the beta agonists alone. Combined therapy produced significant additional improvement in FEV₁ and FVC. On combined therapy, the median duration of 15% improvement in FEV₁ was 5 to 7 hours, compared with 3 to 4 hours in patients receiving a beta agonist alone.

Ipratropium Bromide Inhalation Solution administered either alone or with other bronchodilators, especially beta adrenergics, is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.

Ipratropium bromide is contraindicated in known or suspected cases of hypersensitivity to ipratropium bromide, or to atropine and its derivatives.

The use of Ipratropium Bromide Inhalation Solution as a single agent for the relief of bronchospasm in acute COPD exacerbation has not been adequately studied. Drugs with faster onset of action may be preferable as initial therapy in this situation. Combination of Ipratropium Bromide Inhalation Solution and beta agonists has not been shown to be more effective than either drug alone in reversing the bronchospasm associated with acute COPD exacerbation.

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

Ipratropium bromide should be used with caution in patients with narrow angle glaucoma, prostatic hypertrophy or bladder neck obstruction.

Patients should be advised that mydriasis, temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma or eye pain may result if the solution comes into direct contact with the eyes. Use of a nebulizer with mouthpiece rather than face mask may be preferable, to reduce the likelihood of the nebulizer solution reaching the eyes. Patients should be advised that Ipratropium Bromide Inhalation Solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Ipratropium Bromide Inhalation Solution when mixed with other drugs in a nebulizer have not been established. Patients should be reminded that Ipratropium Bromide Inhalation Solution should be used consistently as prescribed throughout the course of therapy.

Ipratropium bromide has been shown to be a safe and effective bronchodilator when used in conjunction with beta adrenergic bronchodilators. Ipratropium bromide has also been used with other pulmonary medications, including methylxanthines and corticosteroids, without adverse drug interactions.

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at dietary doses up to 6 mg/kg/day of ipratropium bromide.

Results of various mutagenicity studies (Ames test, mouse dominal lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Fertility of male or female rats at oral doses up to 50 mg/kg/day was unaffected by ipratropium bromide administration. At doses above 90 mg/kg, increased resorption and decreased conception rates were observed.

TERATOGENIC EFFECTS

Pregnancy Category B

Oral reproduction studies performed in mice, rats and rabbits at doses of 10, 100, and 125 mg/kg respectively and inhalation reproduction studies in rats and rabbits at doses of 1.5 and 1.8 mg/kg (or approximately 38 and 45 times the recommended human daily dose) respectively, have demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. However, no adequate or well controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, ipratropium bromide should be used during pregnancy only if clearly needed.

It is not known whether ipratropium bromide is excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to a significant extent, especially when taken by inhalation since ipratropium bromide is not well absorbed systemically after inhalation or oral administration. However, because many drugs are excreted in human milk, caution should be exercised when ipratropium bromide is administered to a nursing woman.

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

Adverse reaction information concerning Ipratropium Bromide Inhalation Solution is derived from 12-week active-controlled clinical trials. Additional information is derived from foreign post-marketing experience and the published literature.

All adverse events, regardless of drug relationship, reported by three percent or more patients in the 12-week controlled clinical trials appear in the table.

Additional adverse reactions reported in less than three percent of the patients treated with ipratropium bromide include tachycardia, palpitations, eye pain, urinary retention, urinary tract infection and urticaria. Cases of precipitation or worsening of narrow-angle glaucoma, mydriasis, and acute eye pain have been reported.

Lower respiratory adverse reactions (bronchitis, dyspnea and bronchospasm) were the most common events leading to discontinuation of ipratropium bromide therapy in the 12-week trials. Headache, mouth dryness and aggravation of COPD symptoms are more common when the total daily dose of ipratropium bromide equals or exceeds 2,000 mcg.

Allergic-type reactions such as skin rash, angioedema of tongue, lips and face, urticaria, laryngospasm and anaphylactic reaction have been reported. Many of the patients had a history of allergies to other drugs and/or foods.

Acute systemic overdosage by inhalation is unlikely since ipratropium bromide is not well absorbed after inhalation at up to four-fold the recommended dose, or after oral administration at up to forty-fold the recommended dose. The oral LD₅₀ of ipratropium bromide ranged between 1001 and 2010 mg/kg in mice; between 1667 and 4000 mg/kg in rats; and between 400 and 1300 mg/kg in dogs.

The usual dosage of Ipratropium Bromide Inhalation Solution is 500 mcg (1 Unit-Dose Vial) administered three to four times a day by oral nebulization, with doses 6 to 8 hours apart. Ipratropium Bromide Inhalation Solution Unit-Dose Vials contain 500 mcg ipratropium bromide, USP anhydrous in 2.5 mL normal saline. Ipratropium Bromide Inhalation Solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Ipratropium Bromide Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

Ipratropium Bromide Inhalation Solution is a clear, colorless solution supplied in a unit-dose vial containing 2.5 mL. Supplied in cartons as listed below:

0.02% (0.5 mg/2.5 mL)

         NDC 65862-905-25                    25 vials per carton / 25 vials per foil pouch
         NDC 65862-905-30                    30 vials per carton / 30 vials per foil pouch
         NDC 65862-905-60                    60 vials per carton / 30 vials per foil pouch
         NDC 65862-905-03                    30 vials per carton / 1 vial per foil pouch

Each vial is made from a low density polyethylene (LDPE) resin.

Vials are supplied in a foil pouch.

Store between 15° and 30°C (59° and 86°F). Protect from light. Store in pouch until time of use.

ATTENTION PHARMACIST: Detach “Patient’s Instructions for Use” from Package Insert and dispense with solution.

Ipratropium Bromide Inhalation Solution, 0.02%

Read complete instructions carefully before using.

1. Remove vial from the foil pouch.

Figure 1 (Ipratropium Fig1)

Figure 2 (Ipratropium Fig2)

Figure 3 (Ipratropium Fig3)

Rx only                  NDC 65862-905-01
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)

For Oral Inhalation Only
Not for Injection

1 x 2.5 mL Sterile
Unit Dose Vial

Each low density polyethylene
vial contains: 2.5 mL
Ipratropium Bromide USP
0.02%, preservative free,
isotonic sterile aqueous
solution containing sodium
chloride. Adjusted to pH 3.4 (3
to 4) with hydrochloric acid.
Usual Dosage: See
accompanying prescribing
information. Store between
15° and 30°C (59° and 86°F).
Protect From Light. Store in
pouch until time of use.
ATTENTION PHARMACIST:
Detach “Patient's Instructions
for Use” from Package Insert
and dispense with solution.

Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
IDA, Pashamylaram - 502307, India

M. L. No.: 13/MD/AP/2010/F/R

AUROBINDO

Package Label-principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only                                 NDC 65862-905-25
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)

For Oral Inhalation Only
Not for Injection

25 x 2.5 mL Sterile Unit Dose Vials

Each low density polyethylene vial contains: 2.5 mL Ipratropium
Bromide USP 0.02%, preservative free, isotonic sterile aqueous
solution containing sodium chloride. Adjusted to pH 3.4 (3 to 4)
with hydrochloric acid.
Usual Dosage: See accompanying prescribing information.
Store between 15° and 30°C (59° and 86°F). Protect From Light.
Store unused vials in the foil pouch.
ATTENTION PHARMACIST: Detach “Patient's Instructions for
Use” from Package Insert and dispense with solution.

Manufactured for:                                    M. L. No.: 13/MD/AP/2010/F/R
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
IDA, Pashamylaram - 502307
India

AUROBINDO

Package Label-principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only                                        NDC 65862-905-33
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)

For Oral Inhalation Only
Not for Injection

30 x 2.5 mL Sterile Unit Dose Vials

Each low density polyethylene vial contains: 2.5 mL Ipratropium
Bromide USP 0.02%, preservative free, isotonic sterile aqueous
solution containing sodium chloride. Adjusted to pH 3.4 (3 to 4)
with hydrochloric acid.
Usual Dosage: See accompanying prescribing information.
Store between 15° and 30°C (59° and 86°F). Protect From Light.
Store unused vials in the foil pouch.
ATTENTION PHARMACIST: Detach “Patient's Instructions for
Use” from Package Insert and dispense with solution.

Manufactured for:                                    M. L. No.: 13/MD/AP/2010/F/R
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
IDA, Pashamylaram - 502307
India

AUROBINDO

Package Label-principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only               NDC 65862-905-03
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)
For Oral Inhalation Only
Not for Injection
2.5 mL, Sterile Unit Dose Vial
30 Individually Wrapped Vials
AUROBINDO

Package Label.principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only              NDC 65862-905-25
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)
For Oral Inhalation Only
Not for Injection
25 x 2.5 mL Sterile Unit Dose Vials
AUROBINDO

Package Label.principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only              NDC 65862-905-30
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)
For Oral Inhalation Only
Not for Injection
30 x 2.5 mL Sterile Unit Dose Vials
AUROBINDO

Package Label-principal Display Panel (0.02% (0.5 mg/2.5 mL))

Rx only                     NDC 65862-905-60
Ipratropium Bromide
Inhalation Solution
0.02%
(0.5 mg/2.5 mL)
For Oral Inhalation Only
Not for Injection
60 x 2.5 mL Sterile Unit Dose Vials
(2 x 30 Vial Pouches)
AUROBINDO

Package Label-principal Display Panel (0.02% (0.5 mg/2.5 mL))