ipratropium Br 0.5 MG / albuterol sulfate 3 MG in 3 ML Inhalant Solution

WARNINGS

Paradoxical Bronchospasm: In the clinical study of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, paradoxical bronchospasm was not observed.

However, paradoxical bronchospasm has been observed with both inhaled ipratropium bromide and albuterol products and can be life-threatening.

If this occurs, Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be discontinued immediately and alternative therapy instituted.

DO not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled products containing sympathomimetic amines and with the home use of nebulizers.

Cardiovascular Effects: Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, like other beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms.

Although such effects are uncommon for Ipratropium Bromide and Albuterol Sulfate Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued.

In addition, beta agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression.

The clinical significance of these findings is unknown.

Therefore, Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions to albuterol and/or ipratropium bromide may occur after the administration of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis.

DRUG INTERACTIONS

Drug Interactions Anticholinergic agents : Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications.

Caution is, therefore, advised in the co-administration of Ipratropium Bromide and Albuterol Sulfate Inhalation Solutuion with other drugs having anticholinergic properties.

ß-adrenergic agents : Caution is advised in the co-administration of Ipratropium Bromide and Albuterol Sulfate Inhalation Solutuion and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.

ß-receptor blocking agents : These agents and albuterol sulfate inhibit the effect of each other.

β-receptor blocking agents should be used with caution in patients with hyperreactive airways, and if used, relatively β 1 selective agents are recommended.

Diuretics : The electrocardiogram (ECG) changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β-agonists, especially when the recommended dose of the β-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the co-administration of β-agonist-containing drugs, such as Ipratropium Bromide and Albuterol Sulfate Inhalation Solutuion, with non-potassium sparing diuretics.

Monoamine oxidase inhibitors or tricyclic antidepressants : Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents because the action of albuterol sulfate on the cardiovascular system may be potentiated.

OVERDOSAGE

The effects of overdosage with Ipratropium Bromide and Albuterol Sulfate Inhalation Solution are expected to be related primarily to albuterol sulfate, since ipratropium bromide is not well-absorbed systemically after oral or aerosol administration.

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmia, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of pharmacological effects listed in ADVERSE REACTIONS .

Hypokalemia may also occur.

As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution.

Treatment consists of discontinuation of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution together with appropriate symptomatic therapy.

The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution.

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 540 times the maximum recommended daily inhalation dose of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution on a mg/m 2 basis).

The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 and 2000 mg/kg respectively (approximately 240 and 1100 times the maximum recommended daily inhalation dose of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution on a mg/m 2 basis, respectively).

The inhalation median lethal dose has not been determined in animals.

The oral median lethal dose of ipratropium bromide in mice, rats and dogs is greater than 1000 mg/kg, approximately 1700 mg/kg and approximately 400 mg/kg, respectively (approximately 1400, 4600, and 3600 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis, respectively).

DESCRIPTION

The active components in the product are albuterol sulfate and ipratropium bromide.

Albuterol sulfate, is a salt of racemic albuterol and a relatively selective β 2 -adrenergic bronchodilator chemically described as α 1 -[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α’-diol sulfate (2:1) (salt).

It has a molecular weight of 576.7 and the molecular formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 .

It is a white crystalline powder, soluble in water and slightly soluble in ethanol.

The World Health Organization recommended name for albuterol base is salbutamol.

Figure 3.

1-1.

Chemical structure of albuterol sulfate.

Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo [3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-; a synthetic quaternary ammonium compound, chemically related to atropine.

It has a molecular weight of 430.4 and the empirical formula is C 20 H 30 BrNO 3 •H 2 O.

It is a white crystalline substance, freely soluble in water and lower alcohols, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.

Figure 3.

1-2.

Chemical structure of ipratropium bromide.

Each 3 mL vial of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution contains 3 mg (0.1%) of albuterol sulfate (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide in an isotonic, sterile, aqueous solution containing sodium chloride, hydrochloric acid and/or sodium hydroxide to adjust to pH 4.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution is a clear, colorless solution.

It does not require dilution prior to administration by nebulization.

For Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance.

Using the Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor system, under in-vitro conditions, the mean delivered dose from the mouth piece (% nominal dose) was approximately 46% of albuterol and 42% of ipratropium bromide at a mean flow rate of 3.6 L/min.

The mean nebulization time was 15 minutes or less.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION ).

Figure 3 1-1.

Chemical structure of albuterol sulfate.

Figure 3.

1-2.

Chemical structure of ipratropium bromide.

HOW SUPPLIED

Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg* Inhalation Solution is supplied as 3-mL sterile solution for nebulization in sterile low-density polypropylene unit-dose vials.

Cards of five vials are placed into a foil pouch.

Supplied in cartons as listed below.

*Equivalent to 2.5 mg albuterol base NDC 16252-547-33 30 vials per carton NDC 16252-547-66 60 vials per carton Store between 2°C and 25°C (36°F and 77°F).

Protect from light.

Manufactured by: Catalent Pharma Solutions Woodstock, IL 60098, USA Manufactured for : Cobalt Laboratories Bonita Springs, Florida 34134, USA Item Number: STW-RCO06-42-0003 Revision: 1 Date: November 2008 cobalt logo

GERIATRIC USE

Geriatric Use Of the total number of subjects in clinical studies of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, 62 percent were 65 and over, while 19 percent were 75 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

INDICATIONS AND USAGE

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator.

PEDIATRIC USE

Pediatric Use The safety and effectiveness of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution in patients below 18 years of age have not been established.

PREGNANCY

Pregnancy TERATOGENIC EFFECTS: Pregnancy Category C Albuterol Sulfate : Pregnacy Category C .

Albuterol sulfate has been shown to be teratogenic in mice.

A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m 2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m 2 basis).

The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m 2 basis).

Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).

A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol.

Some of the mothers were taking multiple medications during their pregnancies.

Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Ipratropium Bromide : Pregnancy Category B .

Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis).

Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis).

There are no adequate and well-controlled studies of the use of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, albuterol sulfate, or ipratropium bromide in pregnant women.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether the components of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution are excreted in human milk.

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 as a nebulized solution.

Because of the potential for tumorigenicity shown for albuterol sulfate in some animals, a decision should be made whether to discontinue nursing or discontinue Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, taking into account the importance of the drug to the mother.

INFORMATION FOR PATIENTS

Information for Patients The action of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should last up to 5 hours.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should not be used more frequently than recommended.

Patients should be instructed not to increase the dose or frequency of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution without consulting their healthcare provider.

If symptoms worsen, patients should be instructed to seek medical consultation.

Patients must avoid exposing their eyes to this product as temporary pupillary dilation, blurred vision, eye pain, or precipitation or worsening of narrow-angle glaucoma may occur, and therefore proper nebulizer technique should be assured, particularly if a mask is used.

If a patient becomes pregnant or begins nursing while on Ipratropium Bromide and Albuterol Sulfate Inhalation Solution, they should contact their healthcare provider about use of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution.

See the illustrated Patient’s Instruction for Use in the product package insert.

DOSAGE AND ADMINISTRATION

The recommended dose of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed.

Safety and efficacy of additional doses or increased frequency of administration of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution beyond these guidelines had not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution have not been studied.

The use of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution can be continued as medically indicated to control recurring bouts of bronchospasm.

If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.

A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used to deliver Ipratropium Bromide and Albuterol Sulfate Inhalation Solution to each patient in one U.S.

clinical study.

The safety and efficacy of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution delivered by other nebulizers and compressors have not been established.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.