Combivent Respimat Dailymed

COMBIVENT RESPIMAT 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-methyl-8-(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
The drug product, COMBIVENT RESPIMAT, is composed of a sterile, aqueous solution of ipratropium bromide and albuterol sulfate filled into a 4.5 mL plastic container crimped into an aluminum cylinder (COMBIVENT RESPIMAT cartridge) for use with the COMBIVENT RESPIMAT inhaler. Excipients include water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid. The COMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENT RESPIMAT inhaler. The COMBIVENT RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow moving aerosol cloud of medication from a metered volume of the drug solution. The COMBIVENT RESPIMAT inhaler has an orange-colored cap.
When used with the COMBIVENT RESPIMAT inhaler, each cartridge containing 4 grams of a sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each actuation from the COMBIVENT RESPIMAT inhaler delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) in 11.4 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
Prior to first use, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [ see Patient Counseling Information (17) ].

12clinical Pharmacology

12.1Mechanism of Action

COMBIVENT RESPIMAT: COMBIVENT RESPIMAT is a combination of the anticholinergic ipratropium bromide and the beta₂-adrenergic agonist albuterol sulfate. The mechanisms of action described below for the individual components apply to COMBIVENT RESPIMAT. The two classes of medications (an anticholinergic and a beta₂-adrenergic agonist) are both bronchodilators. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta₂-sympathomimetic (albuterol sulfate) is designed to produce a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. The efficacy of COMBIVENT RESPIMAT is likely to be due to a local effect on the muscarinic and beta₂-adrenergic receptors in the lung.

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.

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 and Precautions (5.2) ].
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, 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 agonist drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients [ see Warnings and Precautions (5.2) ].

12.2Pharmacodynamics

Cardiovascular effects At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.
Ocular effects In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation, or visual acuity.
Mucociliary clearance and respiratory secretions Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions.

Cardiovascular effects Controlled clinical trials and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

12.3Pharmacokinetics

Ipratropium bromide is a quaternary amine and hence, 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.
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.

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.
Intravenous pharmacokinetics of albuterol was 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.

In a 12-week randomized, multicenter, double-blind, double-dummy parallel group trial, 108 US patients with COPD receiving either COMBIVENT RESPIMAT (20/100 mcg) or CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) four times daily participated in pharmacokinetic evaluations. Plasma ipratropium concentrations were low with an average peak plasma concentration of 33.5 pg/mL from COMBIVENT RESPIMAT. The majority of the study participants exhibited levels below the lower limit of quantitation (<10 pg/mL) by 4 to 6 hours following dosing. The steady state systemic exposure obtained for ipratropium bromide following COMBIVENT RESPIMAT was comparable to that of CFC-propelled COMBIVENT Inhalation Aerosol. Ipratropium plasma AUC and total amount of drug excreted unchanged in urine (Ae) ratios for COMBIVENT RESPIMAT/CFC-propelled COMBIVENT Inhalation Aerosol were 1.04 and 1.18, respectively. For albuterol the steady state systemic exposure was less from COMBIVENT RESPIMAT compared to that of CFC-propelled COMBIVENT Inhalation Aerosol. Albuterol plasma AUC and urine Ae ratios for COMBIVENT RESPIMAT/CFC-propelled COMBIVENT Inhalation Aerosol were 0.74 and 0.86, respectively.
Pharmacokinetic drug-drug interaction between ipratropium bromide and albuterol sulfate was evaluated in a crossover study in 12 healthy male volunteers who received CFC-propelled COMBIVENT Inhalation Aerosol and the two active components separately as individual treatments. Results from this study indicated that the coadministration of these two components from a single canister did not significantly alter the systemic absorption of either component, indicating lack of any pharmacokinetic interaction between these two drugs.

Age Consistent with CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg), patients receiving COMBIVENT RESPIMAT (20/100 mcg) aged 65 years and over had higher steady state systemic exposures than patients aged under 65 years for both ipratropium (AUC = 166 vs. 105 pg•hr/mL, C_max = 38.5 vs. 30.1 pg/mL) and albuterol (AUC = 5.44 vs. 3.27 ng•hr/mL, C_max = 1.19 vs. 0.74 ng/mL).
Gender The AUC and C_max values for ipratropium were 131 pg.hr/mL and 35.4 pg/mL in males and 123 pg.hr/mL and 31.7 pg/mL in females, respectively. The AUC- and C_max-values for albuterol were 4.0 ng•hr/mL and 0.89 ng/mL in males and 4.2 ng•hr/mL and 0.93 ng/mL in females, respectively.
Hepatic and Renal Impairment The pharmacokinetics of COMBIVENT RESPIMAT or ipratropium bromide has not been studied in patients with hepatic or renal insufficiency.
Drug-Drug Interactions No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions with other medications.

13nonclinical Toxicology

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg/day (approximately 400 and 200 times the maximum recommended human daily inhalation dose of ipratropium bromide (MRHDID) in adults on a mg/m² basis, respectively).
Results of various mutagenicity/clastogenicity 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/day (approximately 3400 times the MRHDID in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg/day (approximately 34,000 times the MRHDID in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate.

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/day (approximately 20, 110, and 560 times the MRHDID on a mg/m² basis). In another study this effect was blocked by the coadministration 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/day (approximately 2800 times the MRHDID on a mg/m² basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg/day (approximately 470 times the MRHDID 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.

13.2 Animal Toxicology and/or Pharmacology

Preclinical: 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 the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

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 clinical significance of these findings is unknown.

14clinical Studies

The efficacy of COMBIVENT RESPIMAT (20/100 mcg) was evaluated in COPD patients in one randomized, double-blind, double-dummy parallel group trial. This was a 12-week trial in a total of 1460 adult patients (955 males and 505 females) conducted to demonstrate the efficacy and safety of COMBIVENT RESPIMAT (20/100 mcg) in COPD. All patients were required to have a clinical diagnosis of COPD, be at least 40 years of age or older, to have an FEV₁ of less than or equal to 65% predicted and an FEV₁/FVC ratio of less than or equal to 0.7 at screening, and a smoking history of greater than 10 pack-years prior to entering the trial. Patients with narrow-angle glaucoma, symptomatic prostatic hypertrophy, or bladder neck obstruction were excluded from the trial. The majority of the patients (89%) were Caucasian, had a mean age of 64 years, a mean percent predicted pre-bronchodilator FEV₁ of 41% and FEV₁/FVC ratio of 0.45. The patients were randomized to one of the following active treatments COMBIVENT RESPIMAT (20/100 mcg) (n=486), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=491), and ipratropium bromide delivered by the RESPIMAT (20 mcg) (n=483) administered four times a day. Data from 1424 patients were used in the efficacy analyses.
There were three primary efficacy variables: (i) Mean FEV₁ over 0 to 6 hours post-dose defined as the AUC of the change from test-day baseline in FEV₁ over 0 to 6 hours post-dose divided by 6 hours (FEV₁ AUC_0-6h); (ii) Mean FEV₁ over 0 to 4 hours post-dose defined as the AUC of the change from test-day baseline in FEV₁ over 0 to 4 hours post-dose divided by 4 hours (FEV₁ AUC_0-4h), and (iii) Mean FEV₁ over 4 to 6 hours post-dose defined as the AUC of the change from test-day baseline in FEV₁ over 4 to 6 hours post-dose divided by 2 hours (FEV₁ AUC_4-6h). Test-day baseline was the FEV₁ recorded prior to inhaling the dose of randomized treatment on test day.
The three primary efficacy comparisons were: (i) Non-inferiority of COMBIVENT RESPIMAT (20/100 mcg) to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) for the FEV₁ AUC_0-6h on Test Day 85; (ii) Superiority of COMBIVENT RESPIMAT (20/100 mcg) to ipratropium RESPIMAT (20 mcg) for the FEV₁ AUC_0-4h on Test Day 85, to demonstrate the contribution of albuterol in the combination product, and (iii) Non-inferiority of COMBIVENT RESPIMAT (20/100 mcg) in comparison to ipratropium RESPIMAT (20 mcg) for FEV₁ AUC_4-6h on Test Day 85, to demonstrate the contribution of ipratropium in the combination product. Non-inferiority was declared if the lower bound of the 95% confidence interval for the point estimate for the difference of COMBIVENT RESPIMAT minus the comparator was more than -50 mL.
COMBIVENT RESPIMAT (20/100 mcg) was shown to be non-inferior to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) in terms of mean FEV₁ AUC_0-6h. The LS mean (mL) (95% CI) of the treatment difference was -3 (-22, 15). The FEV₁ AUC_0-4h for COMBIVENT RESPIMAT (20/100 mcg), was superior to that of ipratropium bromide [LS mean (mL) (95% CI) of the treatment difference was 47 mL (28, 66)] and the mean FEV₁ AUC_4-6h for COMBIVENT RESPIMAT (20/100 mcg) was non-inferior to that of ipratropium bromide [LS mean (mL) (95% CI) of the treatment difference was -17 (-39, 5)]. The FEV₁ results on Test Days 1, 29, 57, and 85 are shown in Figure 1.
In this trial, COMBIVENT RESPIMAT (20/100 mcg) was shown to be clinically comparable (statistically non-inferior) to CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg).
Additionally, in this trial, no differences in these efficacy comparisons were identified in males and females or in patients over 65 years of age versus those under 65 years of age. There were too few African-American subjects to adequately assess differences in effects in that population.
The median time to onset of bronchodilation, defined as an FEV₁ increase of 15% or greater from test-day baseline, for the COMBIVENT RESPIMAT (20/100 mcg) group occurred at 13 minutes post-dose on Day 1.
The means are adjusted for treatment baseline and investigator site. A separate ANCOVA was fitted for each time point. The imputation method for data missing because the patient withdrew from the trial was Last Visit Carried Forward. The imputation method for data missing at the end of test days depends on why the data were missing.
A second study was conducted in 1118 COPD patients using a higher than approved dose of COMBIVENT RESPIMAT. Patients were randomized to COMBIVENT RESPIMAT (40/200 mcg) (n=345), CFC-propelled COMBIVENT Inhalation Aerosol (36/206 mcg) (n=180), ipratropium delivered by the RESPIMAT (40 mcg) (n=252) or placebo (n= 341). The study was supportive, particularly for safety [ see Adverse Reactions (6.1) ].

16how Supplied/storage And Handling

COMBIVENT RESPIMAT Inhalation Spray is supplied in a carton containing one COMBIVENT RESPIMAT cartridge and one COMBIVENT RESPIMAT inhaler.
The COMBIVENT RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The COMBIVENT RESPIMAT cartridge is only intended for use with the COMBIVENT RESPIMAT inhaler.
The COMBIVENT RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The orange-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the COMBIVENT RESPIMAT cartridge.
COMBIVENT RESPIMAT Inhalation Spray is available as:COMBIVENT RESPIMAT Inhalation Spray: 120 metered actuations (NDC 0597-0024-02))
The COMBIVENT RESPIMAT cartridge has a net fill weight of 4 grams and when used with the COMBIVENT RESPIMAT inhaler, is designed to deliver the labeled number of  metered actuations after preparation for use. Each actuation from the COMBIVENT RESPIMAT inhaler delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) from the mouthpiece.
When the labeled number of metered actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
After assembly, the COMBIVENT RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
Keep out of reach of children. Do not spray into eyes.

Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid freezing.

17patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Paradoxical Bronchospasm
Inform patients that COMBIVENT RESPIMAT can produce paradoxical bronchospasm that can be life-threatening. If paradoxical bronchospasm occurs, patients should discontinue using COMBIVENT RESPIMAT.
Ocular Effects
Caution patients to avoid spraying the aerosol into their eyes and advise 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.
Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of COMBIVENT RESPIMAT, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.
Urinary Retention
Inform patients that COMBIVENT RESPIMAT may cause urinary retention and advise them to consult their physician if they experience difficulty with urination.
Adverse Effects Associated with Beta₂-agonists
Inform patients of adverse effects associated with beta₂-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness [see Warnings and Precautions (5.2, 5.5) ].
Frequency of Use
The action of COMBIVENT RESPIMAT should last 4 to 5 hours or longer. COMBIVENT RESPIMAT should not be used more frequently than recommended. Safety and efficacy of additional doses of COMBIVENT RESPIMAT beyond six inhalations in 24 hours have not been studied. Patients should be told not to increase the dose or frequency of COMBIVENT RESPIMAT without consulting a physician. Patients should be instructed that if they find that treatment with COMBIVENT RESPIMAT becomes less effective for symptomatic relief, their symptoms become worse, and/or they need to use the product more frequently than usual, medical attention should be sought immediately [see Warnings and Precautions (5.5) ].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema, may occur after the administration of COMBIVENT RESPIMAT. Advise patients to immediately discontinue COMBIVENT RESPIMAT and consult a physician [see Warnings and Precautions (5.6) ].
Concomitant Drug Use
Remind patients that while taking COMBIVENT RESPIMAT, other inhaled drugs should be taken only as directed by a physician [see Drug Interactions (7.1) ].
Pregnancy
Patients who are pregnant or nursing should contact their physician about the use of COMBIVENT RESPIMAT [see Use in Specific Populations (8.1, 8.2) ].
Preparation for Use and Priming
Instruct patients that priming COMBIVENT RESPIMAT is essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. COMBIVENT RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA

Licensed from:Boehringer Ingelheim International GmbH
RESPIMAT® is a registered trademark of and used under license from Boehringer Ingelheim International GmbH

COMBIVENT® is a registered trademark of and used under license from Boehringer Ingelheim Pharmaceuticals, Inc.
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