Prescription Drugs

CLINICAL PHARMACOLOGY DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution is a combination of the β2-adrenergic bronchodilator, albuterol sulfate, and the anticholinergic bronchodilator, ipratropium bromide. Albuterol Sulfate Mechanism of Action The prime action of β-adrenergic drugs is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on β2-adrenergic receptors compared with isoproterenol. While it is recognized that β2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicated that 10% to 50% of the βreceptors in the human heart may be β2-receptors. The precise function of these receptors, however, is not yet established. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other β-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients. Pharmacokinetics Albuterol sulfate is longer acting than isoproterenol in most patients by any route of administration, because it is not a substrate for the cellular uptake processes for catecholamine nor for the metabolism of catechol-O-methyl transferase. Instead the drug is conjugatively metabolized to albuterol 4'-O-sulfate. Animal Pharmacology/Toxicology Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside of the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain. Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrythmias and sudden death (with histological evidence of myocardial necrosis) when beta-agonists and methyl-xanthines are administered concurrently. The clinical significance of these findings is unknown. Ipratropium Bromide Mechanism of Action Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which blocks the muscarinic receptors of acetylcholine, and, 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 (cGMP), resulting from the interaction of acetylcholine with the muscarinic receptors of bronchial smooth muscle. Pharmacokinetics The bronchodilation following inhalation of ipratropium is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Following nebulization of a 1-mg dose to healthy volunteers, a mean of 4% of the dose was excreted unchanged in the urine. Ipratropium bromide is minimally (0% to 9% in vitro ) bound to plasma albumin and α1acid glycoproteins. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half is excreted unchanged in the urine. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide that reaches the systemic circulation is reportedly removed by the kidneys rapidly at a rate that exceeds the glomerular filtration rate. The pharmacokinetics of DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution or ipratropium bromide have not been studied in the elderly and in patients with hepatic or renal insufficiency (see PRECAUTIONS). Animal Pharmacology/Toxicology Autoradiographic studies in rats have shown that ipratropium does not penetrate the blood-brain barrier. DuoNeb® (ipratropium bromide and albuterol sulfate) Mechanism of Action DuoNeb (ipratropium bromide and albuterol sulfate) is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: sympathomimetic (albuterol sulfate) and anticholinergic/parasympatholytic (ipratropium bromide). Simultaneous administration of both an anticholinergic and a β2-sympathomimetic is designed to produce greater bronchodilation effects than when either drug is utilized alone at its recommended dosage. Animal Pharmacology/Toxicology In 30-day studies in Sprague-Dawley rats and Beagle dogs, subcutaneous doses of up to 205.5 mcg/kg of ipratropium administered with up to 1000 mcg/kg albuterol in rats and 3.16 mcg/kg ipratropium and 15 mcg/kg albuterol in dogs (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) did not cause death or potentiation of the cardiotoxicity induced by albuterol administered alone. Pharmacokinetics In a double blind, double period, crossover study, 15 male and female subjects were administered single doses of DuoNeb (ipratropium bromide and albuterol sulfate) or albuterol sulfate inhalation solution at two times the recommended single doses as two inhalations separated by 15 minutes. The total nebulized dose of albuterol sulfate from both treatments was 6.0 mg and the total dose of ipratropium bromide from DuoNeb (ipratropium bromide and albuterol sulfate) was 1.0 mg. Peak albuterol plasma concentrations occurred at 0.8 hours after dosing for both treatments. The mean peak albuterol concentration following administration of albuterol sulfate alone was 4.86 (± 2.65) mg/mL and it was 4.65 (± 2.92) mg/mL for DuoNeb (ipratropium bromide and albuterol sulfate) . Mean AUC values for the two treatments were 26.6 (± 15.2) ng·hr/mL (albuterol sulfate alone) versus 24.2 (± 14.5) ng·hr/mL (DuoNeb (ipratropium bromide and albuterol sulfate) ). The mean t½ values were 7.2 (± 1.3) hours (albuterol sulfate alone) and 6.7 (± 1.7) hours (DuoNeb (ipratropium bromide and albuterol sulfate) ). A mean of 8.4 (± 8.9)% of the albuterol dose was excreted unchanged in urine following administration of two vials of DuoNeb (ipratropium bromide and albuterol sulfate) which is similar to 8.8 (± 7.3)% that was obtained from albuterol sulfate inhalation solution. There were no statistically significant differences in the pharmacokinetics of albuterol between the two treatments. For ipratropium, a mean of 3.9 (± 5.1)% of the ipratropium bromide dose was excreted unchanged in urine following two vials of DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution, which is comparable with previously reported data. Clinical Trials In a 12 week, randomized, double-blind, positive-control, crossover study of albuterol sulfate, ipratropium bromide, and DuoNeb (ipratropium bromide and albuterol sulfate) , 863 COPD patients were evaluated for bronchodilator efficacy comparing DuoNeb (ipratropium bromide and albuterol sulfate) with albuterol sulfate and ipratropium bromide alone. DuoNeb (ipratropium bromide and albuterol sulfate) demonstrated significantly better changes in FEV1, as measured from baseline to peak response, when compared with either albuterol sulfate or ipratropium bromide. DuoNeb (ipratropium bromide and albuterol sulfate) was also shown to have the rapid onset associated with albuterol sulfate, with a mean time to peak FEV1 of 1.5 hours, and the extended duration associated with ipratropium bromide with a duration of 15% response in FEV1 of 4.3 hours. Figure 3: 1-3: Mean Change in FEV 1 - Measured on Day 14 This study demonstrated that each component of DuoNeb (ipratropium bromide and albuterol sulfate) contributed to the improvement in pulmonary function, especially during the first 4 to 5 hours after dosing, and that DuoNeb (ipratropium bromide and albuterol sulfate) was significantly more effective than albuterol sulfate or ipratropium bromide alone.

CLINICAL PHARMACOLOGY COMBIVENT Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta2-adrenergic bronchodilator, albuterol sulfate. Mechanism of Action Ipratropium bromide Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released at the neuromuscular junctions in the lung. Anticholinergics prevent the increases in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle. Albuterol sulfate In vitro studies and in vivo pharmacology studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta2-receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet established (see WARNINGS). Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Albuterol has been shown in most clinical trials to have more bronchial smooth muscle relaxation effect than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients (see PRECAUTIONS). COMBIVENT Inhalation Aerosol Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms, anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta2-sympathomimetic (albuterol sulfate) is designed to benefit the patient by producing a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. Pharmacokinetics Ipratropium bromide Much of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies. Plasma levels of ipratropium bromide were below the assay sensitivity limit of 100 pg/mL. The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and α1-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. Albuterol sulfate Albuterol is longer acting than isoproterenol in most patients because it is not a substrate for the cellular uptake processes for catecholamines nor for metabolism by catechol-O-methyl transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-O-sulfate. In a pharmacokinetic study in 12 healthy male volunteers of two inhalations of albuterol sulfate, 103 mcg dose/inhalation through the mouthpiece, peak plasma albuterol concentrations ranging from 419 to 802 pg/mL (mean 599 ± 122 pg/mL) were obtained within three hours post-administration. Following this single-dose administration, 30.8 ± 10.2% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. Since albuterol sulfate is rapidly and completely absorbed, this study could not distinguish between pulmonary and gastrointestinal absorption. Intravenous pharmacokinetics of albuterol were studied in a comparable group of 16 healthy male volunteers; the mean terminal half-life following a 30-minute infusion of 1.5 mg was 3.9 hours with a mean clearance of 439 mL/min/1.73 m². Intravenous albuterol studies in rats demonstrated that albuterol crossed the blood-brain barrier and reached brain concentrations amounting to about 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), the drug achieved concentrations more than 100 times those in whole brain. Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug was transferred to the fetus. Disposition in fetal lungs was comparable to maternal lungs, but fetal liver disposition was 1% of maternal liver levels. Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is unknown. COMBIVENT Inhalation Aerosol In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of two inhalations of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol to the two active components individually, the coadministration of ipratropium bromide and albuterol sulfate from a single canister did not significantly alter the systemic absorption of either component. Ipratropium bromide levels remained below detectable limits ( < 100 pg/mL). Peak albuterol level obtained within 3 hours post-administration was 492 ± 132 pg/mL. Following this single administration, 27.1 ± 5.7% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. From a pharmacokinetic perspective, the synergistic efficacy of COMBIVENT Inhalation Aerosol is likely to be due to a local effect on the muscarinic and beta2-adrenergic receptors in the lung. Special Populations The pharmacokinetics of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly (see PRECAUTIONS). Drug-Drug Interactions No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions. Pharmacodynamics Ipratropium bromide The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation or visual acuity (see ADVERSE REACTIONS). Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure. Clinical Trials In two 12-week randomized, double-blind, active-controlled clinical trials, 1067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of COMBIVENT Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients). Serial FEV1 measurements (shown below as a percent change from test-day baseline) demonstrated that COMBIVENT Inhalation Aerosol produced significantly greater improvement in pulmonary function than either ipratropium bromide or albuterol sulfate when given separately. The median time to onset of a 15% increase in FEV1 was 15 minutes and the median time to peak FEV1 was one hour for COMBIVENT Inhalation Aerosol and its components. The median duration of effect as measured by FEV1 was 4 to 5 hours for COMBIVENT Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate. Percent Change in Adjusted Meana FEV1 from Test-Day Baseline - Endpoint Analysis of the Evaluable Data Set These studies demonstrated that each component of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contributed to the improvement in pulmonary function produced by the combination, especially during the first 4 to 5 hours after dosing, and that COMBIVENT Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone. In the 2 controlled 12-week studies, COMBIVENT Inhalation Aerosol did not produce any change in the secondary efficacy parameters including symptom scores, physician global assessments and morning PEFR, all of which were monitored throughout the study period.

DuoNeb® (ipratropium bromide 0.5 mg/albuterol sulfate 3.0 mg*) Inhalation Solution *Equivalent to 2.5 mg albuterol base DESCRIPTION The active components in DuoNeb® (ipratropium bromide and albuterol sulfate) Inhalation Solution are albuterol sulfate and ipratropium bromide. Albuterol sulfate, is a salt of racemic albuterol and a relatively selective β2-adrenergic bronchodilator chemically described as α1-[(tert-butylamino)methyl]-4-hydroxy-mxylene-α, α'-diol sulfate (2:1) (salt). It has a molecular weight of 576.7 and the empirical formula is (C13H21NO3)2•H2SO4. 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 8azoniabicyclo [3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8methyl-8-(1methylethyl)-, 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 C20H30BrNO3•H2O. 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 DuoNeb (ipratropium bromide and albuterol sulfate) contains 3.0 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 to adjust to pH 4, and edetate disodium, USP (a chelating agent). DuoNeb (ipratropium bromide and albuterol sulfate) is a clear, colorless solution. It does not require dilution prior to administration by nebulization. For DuoNeb (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. DuoNeb (ipratropium bromide and albuterol sulfate) should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION).

Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol Bronchodilator Aerosol For Oral Inhalation Only DESCRIPTION COMBIVENT Inhalation Aerosol is a combination of ipratropium bromide (as the monohydrate) and albuterol sulfate. Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1] octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl8-(1-methylethyl)-, bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound chemically related to atropine. Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons. The structural formula is: C20H30BrNO3•H2O ipratropium bromide Mol. Wt. 430.4 Albuterol sulfate, chemically known as (1,3-benzenedimethanol, α'-[[(1,1dimethylethyl) amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta2-adrenergic bronchodilator. Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. Albuterol sulfate is a white to off-white crystalline powder, freely soluble in water and slightly soluble in alcohol, chloroform, and ether. The structural formula is: (C13H21NO3)2•H2SO4 albuterol sulfate Mol. Wt. 576.7 Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contains a microcrystalline suspension of ipratropium bromide and albuterol sulfate in a pressurized metered-dose aerosol unit for oral inhalation administration. The 200 inhalation unit has a net weight of 14.7 grams. Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece. The excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.

INDICATIONS DuoNeb (ipratropium bromide and albuterol sulfate) is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator. DOSAGE AND ADMINISTRATION The recommended dose of DuoNeb (ipratropium bromide and albuterol sulfate) 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 DuoNeb (ipratropium bromide and albuterol sulfate) beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of DuoNeb (ipratropium bromide and albuterol sulfate) have not been studied. The use of DuoNeb (ipratropium bromide and albuterol sulfate) 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 DuoNeb (ipratropium bromide and albuterol sulfate) to each patient in one U.S. clinical study. The safety and efficacy of DuoNeb (ipratropium bromide and albuterol sulfate) delivered by other nebulizers and compressors have not been established. DuoNeb (ipratropium bromide and albuterol sulfate) should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. HOW SUPPLIED DuoNeb (ipratropium bromide and albuterol sulfate) is supplied as a 3-mL sterile solution for nebulization in sterile low-density polyethylene unit-dose vials. Store in pouch until time of use. Supplied in cartons as listed below. NDC 49502-672-30 30 vials per carton/5 vials per foil pouch NDC 49502-672-60 60 vials per carton/5 vials per foil pouch Store between 2°C and 25°C (36°F and 77°F). Protect from light. DEY®, Napa, CA 94558. FEB 09

INDICATIONS COMBIVENT Inhalation Aerosol is indicated for use in patients with chronic obstructive pulmonary disease (COPD) on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator. DOSAGE AND ADMINISTRATION The dose of COMBIVENT® Inhalation Aerosol is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours. Safety and efficacy of additional doses of COMBIVENT Inhalation Aerosol beyond 12 puffs/24 hours have not been studied. Also, safety and efficacy of extra doses of ipratropium or albuterol in addition to the recommended doses of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol have not been studied. It is recommended to “test-spray” three times before using for the first time and in cases where the aerosol has not been used for more than 24 hours. Avoid spraying into eyes. HOW SUPPLIED COMBIVENT Inhalation Aerosol is supplied as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and an orange protective cap. The COMBIVENT Inhalation Aerosol canister is to be used only with the COMBIVENT Inhalation Aerosol mouthpiece and not with other mouthpieces. This mouthpiece should not be used with other aerosol medications. Each actuation meters 21 mcg of ipratropium bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece. Each 14.7 gram canister provides sufficient medication for 200 actuations (NDC 0597-001314). Warning: The canister should be discarded after the labeled number of actuations has been used. The correct amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. For best results, store the canister at room temperature before use. Avoid excessive humidity. Shake the canister vigorously for at least 10 seconds before use. Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or (800) 459-9906 TTY. Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs): Warning: Contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm public health and the environment by destroying ozone in the upper atmosphere. A notice similar to the above Warning has been placed in the information for the patient of this product under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are any questions about alternatives. Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the inhaler into a fire or incinerator. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Ipratropium bromide licensed from: Boehringer Ingelheim International GmbH. Revised: August 2012

PATIENT INFORMATION DuoNeb® (ipratropium bromide 0.5 mg/albuterol sulfate 3.0 mg*) Inhalation Solution *Equivalent to 2.5 mg albuterol base Patient's Instructions for Use Read this patient information completely every time your prescription is filled as information may have changed. Keep these instructions with your medication as you may want to read them again. DuoNeb (ipratropium bromide and albuterol sulfate) should only be used under the direction of a physician. Your physician and pharmacist have more information about DuoNeb (ipratropium bromide and albuterol sulfate) and the condition for which it has been prescribed. Contact them if you have additional questions. Storing your Medicine Store DuoNeb (ipratropium bromide and albuterol sulfate) between 2°C and 25°C (36°F and 77°F). Vials should be protected from light before use, therefore, keep unused vials in the foil pouch or carton. Do not use after the expiration (EXP) date printed on the carton. Dose DuoNeb (ipratropium bromide and albuterol sulfate) is supplied as a single-dose, ready-to-use vial containing 3 mL of solution. No mixing or dilution is needed. Use one new vial for each nebulizer treatment. FOLLOW THESE DIRECTIONS FOR USE OF YOUR NEBULIZER/COMPRESSOR OR THE DIRECTIONS GIVEN BY YOUR HEALTHCARE PROVIDER. A TYPICAL EXAMPLE IS SHOWN BELOW. Instructions for Use 1. Remove one vial from the foil pouch. Place remaining vials back into pouch for storage. 2. Twist the cap completely off the vial and squeeze the contents into the nebulizer reservoir (Figure 1). Figure 1 3. Connect the nebulizer to the mouthpiece or face mask (Figure 2). Figure 2 4. Connect the nebulizer to the compressor. 5. Sit in a comfortable, upright position; place the mouthpiece in your mouth (Figure 3) or put on the face mask (Figure 4); and turn on the compressor. Figure 3 Figure 4 6. Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer chamber (about 5-15 minutes). At this point, the treatment is finished. 7. Clean the nebulizer (see manufacturer's instructions). DuoNeb® (DOO-o-neb) (Ipratropium Bromide 0.5 mg/Albuterol Sulfate 3.0 mg*) Inhalation Solution *Equivalent to 2.5 mg albuterol base Read the patient information that comes with DuoNeb® (ipratropium bromide and albuterol sulfate) before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What is DuoNeb® (ipratropium bromide and albuterol sulfate) ? DuoNeb® (ipratropium bromide and albuterol sulfate) is a combination of two medicines called bronchodilators. DuoNeb® (ipratropium bromide and albuterol sulfate) contains albuterol sulfate, which is a beta-adrenergic agonist, and ipratropium bromide, which is an anticholinergic. These two medicines work together to help open the airways in your lungs. DuoNeb® (ipratropium bromide and albuterol sulfate) is used to help treat airway narrowing (bronchospasm) that happens with chronic obstructive pulmonary disease (COPD) in adult patients who need to use more than one bronchodilator medicine. Who should not use DuoNeb® (ipratropium bromide and albuterol sulfate) ? Do not use DuoNeb® (ipratropium bromide and albuterol sulfate) if you: Are allergic to any of the ingredients in DuoNeb (ipratropium bromide and albuterol sulfate) or to atropine. The active ingredients are albuterol sulfate and ipratropium bromide. See the end of this leaflet for a complete list of ingredients in DuoNeb® (ipratropium bromide and albuterol sulfate) . DuoNeb® (ipratropium bromide and albuterol sulfate) has not been studied in patients younger than 18 years of age. What should I tell my doctor before I start using DuoNeb® (ipratropium bromide and albuterol sulfate) ? Tell your doctor about all of your conditions, including if you: Have heart problems. This includes coronary artery disease and heart rhythm problems. Have high blood pressure Have diabetes Have or had seizures Have a thyroid problem called hyperthyroidism Have an eye problem called narrow-angle glaucoma Have liver or kidney problems Have problems urinating due to bladder-neck blockage or an enlarged prostate (men) Are pregnant or planning to become pregnant. It is not known if DuoNeb® (ipratropium bromide and albuterol sulfate) can harm your unborn baby. You and your doctor will have to decide if DuoNeb® (ipratropium bromide and albuterol sulfate) is right for you during a pregnancy. Are breastfeeding. It is not known if DuoNeb® (ipratropium bromide and albuterol sulfate) passes into your milk or if it can harm your baby. You and your doctor should decide whether you should take DuoNeb® (ipratropium bromide and albuterol sulfate) or breastfeed, but not both. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. DuoNeb® (ipratropium bromide and albuterol sulfate) and other medicines can interact. This may cause serious side effects. Especially tell your doctor if you take: Other medicines that contain anticholinergics such as ipratropium bromide. This also includes medicines used for Parkinson's disease. Other medicines that contain beta-agonists such as albuterol sulfate. These are usually used to treat airway narrowing (bronchospasm). Medicines called beta-blockers. These are usually used for high blood pressure or heart problems. Medicines called “water pills” (diuretics) Medicines for depression called monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants. Ask your doctor or pharmacist if you are not sure if you take any of these types of medicines. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacists when you get a new medicine. How should I use DuoNeb® (ipratropium bromide and albuterol sulfate) ? Read the Patient's Instructions for Use that you get with your prescription. Talk to your doctor or pharmacist if you have any questions. Take DuoNeb® (ipratropium bromide and albuterol sulfate) exactly as prescribed by your doctor. Do not change your dose or how often you use DuoNeb® (ipratropium bromide and albuterol sulfate) without talking to your doctor. Inhale DuoNeb® (ipratropium bromide and albuterol sulfate) through your mouth and into your lungs using a machine called a nebulizer. DuoNeb® (ipratropium bromide and albuterol sulfate) may help to open your airways for up to 5 hours after taking this medicine. If DuoNeb® (ipratropium bromide and albuterol sulfate) does not help your airway narrowing (bronchospasm) or your bronchospasm gets worse, call your doctor right away or get emergency help if needed. What should I avoid while using DuoNeb® (ipratropium bromide and albuterol sulfate) ? Do not get DuoNeb® (ipratropium bromide and albuterol sulfate) in your eyes. Be careful not to spray DuoNeb® (ipratropium bromide and albuterol sulfate) in your eyes while you are using your nebulizer. DuoNeb® (ipratropium bromide and albuterol sulfate) can cause the following short-term eye problems: Enlarged pupils Blurry vision Eye pain DuoNeb® (ipratropium bromide and albuterol sulfate) can cause a serious eye problem called narrow-angle glaucoma or worsen the narrow-angle glaucoma you already have. What are the possible side effects with DuoNeb® (ipratropium bromide and albuterol sulfate) ? DuoNeb® (ipratropium bromide and albuterol sulfate) may cause the following serious side effects: Worsening of the narrowing in your airways (bronchospasm). This side effect can be life-threatening and has happened with both of the medicines that are in DuoNeb® (ipratropium bromide and albuterol sulfate) . Stop DuoNeb® (ipratropium bromide and albuterol sulfate) and call your doctor right away or get emergency help if your breathing problems get worse while or after using DuoNeb® (ipratropium bromide and albuterol sulfate) . Serious and life-threatening allergic reactions. Symptoms of a serious allergic reaction include: Hives, rash Swelling of your face, eyelids, lips, tongue, or throat, and trouble swallowing Worsening of your breathing problems such as wheezing, chest tightness or shortness of breath Shock (loss of blood pressure and consciousness) The most common side effects with DuoNeb® (ipratropium bromide and albuterol sulfate) include lung disease, sore throat, chest pain, constipation, diarrhea, bronchitis, urinary tract infection, leg cramps, nausea, upset stomach, voice changes, and pain. These are not all the side effects with DuoNeb® (ipratropium bromide and albuterol sulfate) . For a complete list, ask your doctor or pharmacist. How should I store DuoNeb® (ipratropium bromide and albuterol sulfate) ? Store DuoNeb® (ipratropium bromide and albuterol sulfate) between 36° and 77°F (2° and 25°C). Protect from light. Keep the unused vials in the foil pouch or carton. Safely discard DuoNeb® (ipratropium bromide and albuterol sulfate) that is out-of-date or no longer needed. Keep DuoNeb® (ipratropium bromide and albuterol sulfate) and all medicines out of the reach of children. General advice about DuoNeb® (ipratropium bromide and albuterol sulfate) Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflets. Do not use DuoNeb® (ipratropium bromide and albuterol sulfate) for a condition for which it was not prescribed. Do not give DuoNeb® (ipratropium bromide and albuterol sulfate) to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about DuoNeb® (ipratropium bromide and albuterol sulfate) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DuoNeb® (ipratropium bromide and albuterol sulfate) that is written for healthcare professionals. You can also call the company that makes DuoNeb® (ipratropium bromide and albuterol sulfate) toll free at 1-800-755-5560 or visit their website at www.dey.com. What are the ingredients in DuoNeb®? Active Ingredients: ipratropium bromide and albuterol sulfate Inactive Ingredients: sodium chloride, hydrochloric acid, and edetate sodium, USP.

PATIENT INFORMATION Patient's Instructions for Use Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol Read complete instructions carefully before using Use COMBIVENT Inhalation Aerosol exactly as prescribed by your doctor. Do not change your dose or how often you use COMBIVENT Inhalation Aerosol without talking with your doctor. Talk to your doctor if you have questions about your medical condition or your treatment. Tell your doctor about all of the medicines you take. COMBIVENT Inhalation Aerosol and some other medicines may interact with each other. Do not use other inhaled medicines with COMBIVENT Inhalation Aerosol unless prescribed by your doctor. 1. Insert metal canister into clear end of mouthpiece (see Figure 1). Make sure the canister is fully and firmly inserted into the mouthpiece. The COMBIVENT Inhalation Aerosol canister is to be used only with the COMBIVENT Inhalation Aerosol mouthpiece. This mouthpiece should not be used with other inhaled medicines. Figure 1 2. Remove orange protective dust cap. If the cap is not on the mouthpiece, make sure there is nothing in the mouthpiece before use. For best results, the canister should be at room temperature before use. 3. Shake and Test Spray. Perform this step before using for the first time, and whenever the aerosol has not been used for more than 24 hours; otherwise, proceed directly to Step 4. After vigorously shaking the canister for at least 10 seconds (see step 4 for instructions on shaking), “test-spray” into the air 3 times. Avoid spraying in eyes. 4. Shake the canister vigorously for at least 10 seconds. Hold canister as illustrated in Figure 2. IMPORTANT: Vigorous shaking for at least 10 seconds before each spray is very important for proper product performance. For best results, perform Steps 5 and 6 within 30 seconds of shaking the canister. Figure 2 5. Breathe out (exhale) deeply through your mouth. Holding the canister upright as shown in Figure 3, between your thumb and finger(s), put the mouthpiece in your mouth and close your lips. Keep your eyes closed so that no medicine will be sprayed into your eyes. Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol can cause blurry vision, narrow-angle glaucoma or worsening of this condition or eye pain if the medicine is sprayed into your eyes. Figure 3 6. Breathe in (inhale) slowly through your mouth and at the same time spray the product into your mouth. To spray the product, firmly press once on the canister against the mouthpiece as shown in Figure 4. Keep breathing in deeply. Figure 4 7. Hold your breath for 10 seconds, remove the mouthpiece from your mouth and breathe out slowly, as in Figure 5. Figure 5 8. Wait approximately 2 minutes, shake the inhaler vigorously for at least 10 seconds again (as described in Step 4), and repeat Steps 5 to 7. 9. Replace the orange protective dust cap after use. 10. Keep the mouthpiece clean. Wash with hot water. If soap is used, rinse thoroughly with plain water. Dry thoroughly before use. When dry, replace cap on the mouthpiece when not using the drug product. 11. Keep track of the number of sprays used and discard after 200 sprays. Even though the canister is not empty, you cannot be sure of the amount of medicine in each spray after 200 sprays. 12. If your prescribed dose does not provide relief or your breathing symptoms become worse, get medical help right away. Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs): This product contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm the environment by destroying ozone in the upper atmosphere. The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture the canister. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator. Keep COMBIVENT Inhalation Aerosol out of reach of children. Avoid spraying in eyes. Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or (800) 459-9906 TTY. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. For best results, store the canister at room temperature before use. Avoid excessive humidity.

OVERDOSE The effects of overdosage with DuoNeb (ipratropium bromide and albuterol sulfate) 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 DuoNeb (ipratropium bromide and albuterol sulfate) . Treatment consists of discontinuation of DuoNeb (ipratropium bromide and albuterol sulfate) 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 DuoNeb (ipratropium bromide and albuterol sulfate) . 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 DuoNeb (ipratropium bromide and albuterol sulfate) on a mg/m² 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 DuoNeb (ipratropium bromide and albuterol sulfate) on a mg/m² 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/m² basis, respectively). CONTRAINDICATIONS DuoNeb (ipratropium bromide and albuterol sulfate) is contraindicated in patients with a history of hypersensitivity to any of its components, or to atropine and its derivatives.

OVERDOSE The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with ipratropium bromide by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after aerosol or oral administration. Oral median lethal doses of ipratropium bromide were greater than 1001 mg/kg in mice (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis); 1663 mg/kg in rats (approximately 62,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis); and 400 mg/kg in dogs (approximately 50,000 times the maximum recommended daily inhalation dose in adults, on a mg/m² basis). Whereas the oral median lethal dose of albuterol sulfate in mice and rats was greater than 2000 mg/kg (approximately 6600 and 13,000 times the maximum recommended daily inhalation dose, respectively, in adults on a mg/m² basis), the inhalational median lethal dose could not be determined. Manifestations of overdosage with albuterol may include anginal pain, hypertension, hypokalemia, tachycardia with rates up to 200 beats per minute, metabolic acidosis, and exaggeration of the pharmacologic effects listed in ADVERSE REACTIONS. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse. Dialysis is not appropriate treatment for overdosage of albuterol as an inhalation aerosol; the judicious use of a cardiovascular beta-receptor blocker, such as metoprolol tartrate may be indicated. CONTRAINDICATIONS COMBIVENT Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. COMBIVENT Inhalation Aerosol is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine or its derivatives.

SIDE EFFECTS Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for COMBIVENT Inhalation Aerosol) as seen in Table 1. Table 1 : All Adverse Events (in percentages), from Two Large Double-blind, Parallel, 12-Week Studies of Patients with COPD* COMBIVENT Ipratropium Bromide 36 mcg/Albuterol Sulfate 206 mcg QID N = 358 Ipratropium Bromide 36 mcg QID N = 362 Albuterol Sulfate 206 mcg QID N = 347 Body as a Whole-General Disorders Headache 5.6 3.9 6.6 Pain 2.5 1.9 1.2 Influenza 1.4 2.2 2.9 Chest Pain 0.3 1.4 2.9 Gastrointestinal System Disorders Nausea 2.0 2.5 2.6 Respiratory System Disorders (Lower) Bronchitis 12.3 12.4 17.9 Dyspnea 4.5 3.9 4 Coughing 4.2 2.8 2.6 Respiratory Disorders 2.5 1.7 2.3 Pneumonia 1.4 2.5 0.6 Bronchospasm 0.3 3.9 1.7 Respiratory System Disorders (Upper) Upper Respiratory Tract Infection 10.9 12.7 13 Pharyngitis 2.2 3.3 2.3 Sinusitis 2.3 1.9 0.9 Rhinitis 1.1 2.5 2.3 *All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group in the 12-week controlled clinical trials. Additional adverse reactions, reported in less than two percent of the patients in the COMBIVENT Inhalation Aerosol treatment group include edema, fatigue, hypertension, dizziness, nervousness, paresthesia, tremor, dysphonia, insomnia, diarrhea, dry mouth, dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased sputum, taste perversion, and urinary tract infection/dysuria. Allergic-type reactions such as skin reactions including rash, pruritus, and urticaria (including giant urticaria), angioedema including that of tongue, lips and face, laryngospasm and anaphylactic reaction have been reported with Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, with positive rechallenge in some cases. Many of these patients had a history of allergies to other drugs and/or foods including soybean (see CONTRAINDICATIONS). Post-Marketing Experience In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving Atrovent® (ipratropium bromide) Inhalation Aerosol CFC. Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: hypersensitivity, pharyngeal edema, mouth edema, urinary retention, mydriasis, bronchospasm (including paradoxical bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, intraocular pressure increased, acute eye pain, halo vision, blurred vision, accommodation disorder, ocular irritation, corneal edema, conjunctival hyperaemia, nasal congestion, drying of secretions, mucosal ulcers, stomatitis, irritation from aerosol, throat irritation, dry throat, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations, heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), gastrointestinal motility disorder, constipation, hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia, asthenia, myocardial ischemia, diastolic blood pressure decreased, and systolic blood pressure increased. Metabolic acidosis has been reported with use of albuterol-containing products. DRUG INTERACTIONS COMBIVENT Inhalation Aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids, commonly used in the treatment of chronic obstructive pulmonary disease. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of COMBIVENT Inhalation Aerosol and these drugs with respect to safety and effectiveness. Anticholinergic agents There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of COMBIVENT Inhalation Aerosol with other anticholinergic-containing drugs. Beta-adrenergic agents Caution is advised in the co-administration of COMBIVENT Inhalation Aerosol and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects. Beta-receptor blocking agents and albuterol inhibit the effect of each other. Beta-receptor blocking agents should be used with caution in patients with hyperreactive airways. Diuretics The ECG changes and/or hypokalemia which may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonist-containing drugs, such as COMBIVENT Inhalation Aerosol, with non-potassium sparing diuretics. Consider monitoring potassium levels. Monoamine oxidase inhibitors or tricyclic antidepressants COMBIVENT Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or within two weeks of discontinuation of such agents because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.

WARNINGS Paradoxical Bronchospasm In the clinical study of DuoNeb (ipratropium bromide and albuterol sulfate) , 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, DuoNeb (ipratropium bromide and albuterol sulfate) 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 Effect DuoNeb (ipratropium bromide and albuterol sulfate) , 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 DuoNeb (ipratropium bromide and albuterol sulfate) 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, DuoNeb (ipratropium bromide and albuterol sulfate) , 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 DuoNeb (ipratropium bromide and albuterol sulfate) as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis. PRECAUTIONS General Effects Seen with Sympathomimetic Drugs: As with all products containing sympathomimetic amines, DuoNeb (ipratropium bromide and albuterol sulfate) should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Additionally, β-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting. The decrease is usually transient, not requiring supplementation. Effects Seen with Anticholinergic Drugs: Due to the presence of ipratropium bromide in DuoNeb (ipratropium bromide and albuterol sulfate) , it should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction. Use in Hepatic or Renal Disease: DuoNeb (ipratropium bromide and albuterol sulfate) has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in these patient populations. Information for Patients The action of DuoNeb (ipratropium bromide and albuterol sulfate) should last up to 5 hours. DuoNeb (ipratropium bromide and albuterol sulfate) should not be used more frequently than recommended. Patients should be instructed not to increase the dose or frequency of DuoNeb (ipratropium bromide and albuterol sulfate) 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 papillary 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 DuoNeb (ipratropium bromide and albuterol sulfate) , they should contact their healthcare provider about use of DuoNeb. See the illustrated Patient's Instruction for Use in the product package insert. Carcinogenesis, Mutagenesis, Impairment of Fertility Albuterol sulfate In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m² basis). In another study, this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleous assay. Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Ipratropium bromide In 2-year studies in Sprague-Dawley rats and CD-1 mice, ipratropium bromide showed no evidence of tumorigenicity at oral doses up to 6 mg/kg (approximately 15 times and 8 times the maximum recommended daily inhalation dose for adults in rats and mice respectively, on a mg/m² basis). Ipratropium bromide was not mutagenic in the Ames test and mouse dominant lethal test. Ipratropium bromide was not clastogenic in a mouse micronucleous assay. A reproduction study in rats demonstrated decreased conception and increased resorptions when ipratropium bromide was administered orally at a dose of 90 mg/kg (approximately 240 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). These effects were not seen with a dose of 50 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Pregnancy Teratogenic Effects: Pregnancy Category C Albuterol sulfate Pregnancy 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/m² 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/m² 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/m² 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/m² 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/m² 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/m² basis). There are no adequate and well-controlled studies of the use of DuoNeb (ipratropium bromide and albuterol sulfate) , albuterol sulfate, or ipratropium bromide in pregnant women. DuoNeb (ipratropium bromide and albuterol sulfate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Oral albuterol sulfate has been shown to delay preterm labor in some reports. Because of the potential of albuterol to interfere with uterine contractility, use of DuoNeb (ipratropium bromide and albuterol sulfate) during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Nursing Mothers It is not known whether the components of DuoNeb (ipratropium bromide and albuterol sulfate) 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 DuoNeb (ipratropium bromide and albuterol sulfate) , taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of DuoNeb (ipratropium bromide and albuterol sulfate) in patients below 18 years of age have not been established. Geriatric Use Of the total number of subjects in clinical studies of DuoNeb (ipratropium bromide and albuterol sulfate) , 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.

WARNINGS Paradoxical Bronchospasm: COMBIVENT Inhalation Aerosol can produce paradoxical bronchospasm that can be life-threatening. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister. Cardiovascular Effect: The albuterol sulfate contained in COMBIVENT Inhalation Aerosol, 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. If these symptoms occur, discontinuation of the drug may be indicated. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol. In addition, beta-adrenergic agents have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. Therefore, COMBIVENT Inhalation Aerosol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension. Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of ipratropium bromide or albuterol sulfate, as demonstrated by urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. If such a reaction occurs, therapy with COMBIVENT Inhalation Aerosol should be stopped at once and alternative treatment should be considered. Storage Conditions: The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator. Keep out of reach of children. PRECAUTIONS General Effects Seen with Anticholinergic Drugs: COMBIVENT Inhalation Aerosol contains ipratropium bromide and, therefore, should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction. Effects Seen with Sympathomimetic Drugs: Preparations containing sympathomimetic amines such as albuterol sulfate should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Beta-adrenergic agents may also produce significant hypokalemia in some patients (possibly through intracellular shunting) which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Use in Hepatic or Renal Disease: COMBIVENT Inhalation Aerosol has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations. Information for Patients Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately. The action of COMBIVENT Inhalation Aerosol should last 4 to 5 hours or longer. COMBIVENT Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of COMBIVENT Inhalation Aerosol without consulting your physician. If you find that treatment with COMBIVENT Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking COMBIVENT Inhalation Aerosol, other inhaled drugs should be taken only as directed by your physician. If you are pregnant or nursing, contact your physician about use of COMBIVENT Inhalation Aerosol. Appropriate use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an understanding of the way it should be administered (see Patient's Instructions for Use). Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of COMBIVENT, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery. Carcinogenesis, Mutagenesis, Impairment of Fertility Ipratropium bromide Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 230 and 110 times the maximum recommended daily inhalation dose of ipratropium bromide in adults, respectively, on a mg/m² basis. 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 at oral doses up to 50 mg/kg (approximately 1900 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 19,000 times the maximum recommended daily inhalation dose in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate. Albuterol Like other agents in its class, albuterol caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a 2-year study in the rat at dietary doses of 2, 10, and 50 mg/kg (approximately 15, 65, and 330 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). In another study this effect was blocked by the co-administration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg (approximately 1600 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg (approximately 220 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) revealed no evidence of tumorigenicity. Studies with albuterol revealed no evidence of mutagenesis. Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility. Pregnancy COMBIVENT Inhalation Aerosol Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, ipratropium bromide or albuterol sulfate, in pregnant women. Animal reproduction studies have not been conducted with COMBIVENT Inhalation Aerosol. However, albuterol sulfate has been shown to be teratogenic in mice and rabbits. COMBIVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ipratropium bromide Teratogenic Effects Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats, and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to approximately 190, 38,000, and 9400 times the maximum recommended daily inhalation dose in adults on a mg/m² basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg (approximately 55 and 140 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 3,400 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration. Albuterol Teratogenic Effects Albuterol has been shown to be teratogenic in mice and rabbits. A reproduction study in CD-1 mice given albuterol subcutaneously (0.025, 0.25, and 2.5 mg/kg) showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (equivalent to the maximum recommended daily inhalation dose in adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). None was observed at 0.025 mg/kg (less than the maximum recommended daily inhalation dose in adults). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol (positive control). A reproduction study with oral albuterol in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg (approximately 660 times the maximum recommended daily inhalation dose in adults on a mg/m² basis). Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol for the treatment of COPD during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Nursing Mothers It is not known whether the components of COMBIVENT Inhalation Aerosol are excreted in human milk. Ipratropium bromide Because lipid-insoluble quaternary cations pass into breast milk, caution should be exercised when COMBIVENT Inhalation Aerosol is administered to a nursing mother. Albuterol Because of the potential for tumorigenicity shown for albuterol in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in the pediatric population have not been established.