Albuterol; Ipratropium Bromide (3214)
| Ingredients: |
Albuterol; Ipratropium Bromide |
| Indications: |
Bronchitis, chronic; Emphysema; Chronic obstructive pulmonary disease |
| Pregnancy Category: |
C |
| FDA Approved: |
1996- 10- 01 |
| Classes: |
Adrenergic agonists; Anticholinergics; Bronchodilators |
| HCFA Jcodes: |
J7621 |
| Brand Names: |
Albugenol TR
-
Dominican-republic, El-salvador, Guatemala, Honduras
;
Combivent
-
US; Argentina, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Denmark, England, France, Hong-kong, Indonesia, Ireland, Korea, Mexico, Paraguay, Peru, Philippines, Thailand, Uruguay, Venezuela
;
Combivent Aerosol
-
AUSTRALIA
;
Di-Promal
-
Austria
;
Duolin
-
Australia, India
;
DuoNeb
-
US
;
Duospirel
-
Austria
;
|
| DEA schedules: |
(none)
|
DESCRIPTION
|
| |
Combivent inhalation aerosol is a combination of albuterol sulfate and ipratropium bromide. 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 (endo, syn)- , (±): a synthetic quaternary ammonium compound chemically related
to atropine. Ipratropium bromide is a white to off- white crystalline substance soluble in water and lower alcohols but insoluble
in lipophilic solvents such as ether, chloroform and fluorocarbons. The chemical formula is C20 H30 BrNO3 ·H2 O, and the molecular weight is 430.4.
Albuterol sulfate, chemically known as (1, 3- benzenedimethanol, a′- [[(1, 1- dimethylethyl)amino]methyl]- 4- hydroxy, sulfate
(2:1)(salt), (±)- , is a relatively selective beta2 - adrenergic bronchodilator. Albuterol is the official generic name in the US. The World Health Organization's recommended
name for the drug is salbutamol. Albuterol sulfate is a white to off- white crystalline powder soluble in water and slightly
soluble in ethanol. The chemical formula is (C13 H21 NO3 )2 ·H2 SO4 , and the molecular weight is 576.7.
Combivent Inhalation Aerosol contains a microcrystalline suspension of albuterol sulfate; ipratropium bromide 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 120 μg of albuterol sulfate and 21 μg of ipratropium bromide from the valve and delivers 103 μg of albuterol
sulfate (equivalent to 90 μg albuterol base) and 18 μg of ipratropium bromide from the mouthpiece. The excipients are dichlorodifluoromethane,
dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.
|
CLINICAL PHARMACOLOGY
|
| |
Albuterol sulfate; ipratropium bromide inhalation aerosol is a combination of the anticholinergic bronchodilator, ipratropium
bromide, and the beta2 - adrenergic bronchodilator, albuterol sulfate.
Albuterol Sulfate
|
| |
Mechanism of Action
|
| |
In vitro and in vivo pharmacologic 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 that 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, results
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 the 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 ).
|
Pharmacokinetics
|
| |
Albuterol is longer acting than isoproterenol in most patients, because it is neither 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 2 inhalations of albuterol sulfate, 103 μg dose/ inhalation through
the mouthpiece, peak plasma albuterol concentrations ranging from 419- 802 pg/ ml (mean 599 ± 122 pg/ ml) were obtained within
3 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 (IV) 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.
|
|
Ipratropium Bromide
|
| |
Mechanism of Action
|
| |
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 from the vagus nerve. Anticholinergics
prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP), which are caused by interaction
of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
|
Pharmacokinetics
|
| |
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site- specific effect, not a systemic
one. 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 IV administration. Ipratropium bromide is minimally bound
(0- 9% in vitro ) to plasma albumin and alpha1 - 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. Studies in rats have shown that ipratropium bromide
does not penetrate the blood- brain barrier. The pharmacokinetics of albuterol sulfate; ipratropium bromide inhalation aerosol
or ipratropium bromide have not been studied in elderly patients or those with hepatic or renal insufficiency (see PRECAUTIONS ).
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.
|
|
Albuterol Sulfate; Ipratropium Bromide Inhalation Aerosol
|
| |
Mechanism of Action
|
| |
Albuterol sulfate; ipratropium bromide 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
|
| |
In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of 2
inhalations of albuterol sulfate; ipratropium bromide inhalation aerosol to the 2 active components individually, the coadministration
of albuterol sulfate; ipratropium bromide 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 albuterol sulfate;
ipratropium bromide inhalation aerosol is likely to be due to a local effect on the muscarinic and beta2 - adrenergic receptors in the lung.
|
|
|
CLINICAL STUDIES
|
| |
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 albuterol sulfate; ipratropium bromide inhalation aerosol
(358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients).
Serial FEV1 measurements (percent change from test- day baseline) demonstrated that albuterol sulfate; ipratropium bromide inhalation
aerosol produced significantly greater improvement in pulmonary function than either albuterol sulfate or ipratropium bromide
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 1 hour for albuterol sulfate; ipratropium bromide inhalation aerosol and its components. The median duration of effect
as measured by FEV1 was 4- 5 hours for albuterol sulfate; ipratropium bromide inhalation aerosol compared to 3 hours for albuterol sulfate and
4 hours for ipratropium bromide.
Studies demonstrated that each component of albuterol sulfate; ipratropium bromide inhalation aerosol contributed to the improvement
in pulmonary function produced by the combination, especially during the first 4- 5 hours after dosing. Albuterol sulfate;
ipratropium bromide inhalation aerosol was significantly more effective than albuterol sulfate or ipratropium bromide administered
alone.
In the two controlled 12 week studies, albuterol sulfate; ipratropium bromide 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.
|
INDICATIONS AND USAGE
|
| |
Albuterol sulfate; ipratropium bromide 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 require a second bronchodilator.
|
CONTRAINDICATIONS
|
| |
Albuterol sulfate; ipratropium bromide inhalation aerosol is contraindicated in patients with a history of hypersensitivity
to soya lecithin or related food products, such as soybean and peanut. Albuterol sulfate; ipratropium bromide inhalation aerosol
is also contraindicated in patients hypersensitive to any other components of the drug product or to atropine and/ or its
derivatives.
|
WARNINGS
|
| |
Paradoxical Bronchospasm
|
| |
Albuterol sulfate; ipratropium bromide 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 albuterol sulfate; ipratropium bromide 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. Although such effects are uncommon after administration of albuterol sulfate; ipratropium bromide inhalation
aerosol at recommended doses, if they occur, discontinuation of the drug may be indicated. In addition, beta- adrenergic agents
have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment
depression. Therefore, albuterol sulfate; ipratropium bromide 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 albuterol sulfate or ipratropium bromide, as demonstrated
by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis and oropharyngeal edema.
|
Storage Conditions
|
| |
The contents of albuterol sulfate; ipratropium bromide 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
|
| |
Albuterol sulfate; ipratropium bromide inhalation aerosol contains ipratropium bromide and, therefore, should be used with
caution in patients with narrow- angle glaucoma, prostatic hypertrophy 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 Renal and Hepatic Disease
|
| |
Albuterol sulfate; ipratropium bromide 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 the Patient
|
| |
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, eye pain or discomfort, temporary blurring of vision, visual halos, or colored images
in association with red eyes from conjunctival and corneal congestion. Should any combination of these symptoms develop, consult
your physician immediately.
The action of albuterol sulfate; ipratropium bromide inhalation aerosol should last 4- 5 hours or longer. Albuterol sulfate;
ipratropium bromide inhalation aerosol should not be used more frequently than recommended. Do not increase the dose or frequency
of albuterol sulfate; ipratropium bromide inhalation aerosol without consulting your physician. If you find that treatment
with albuterol sulfate; ipratropium bromide 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 albuterol sulfate; ipratropium bromide 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 albuterol sulfate; ipratropium
bromide inhalation aerosol. Appropriate use of albuterol sulfate; ipratropium bromide inhalation aerosol includes an understanding
of the way it should be administered (refer to the Patient Instructions that you will receive with your prescription for complete
instructions).
|
Carcinogenesis, Mutagenesis, and Impairment of Fertility
|
| |
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/ day (approximately 20, 100, and 500
times, respectively, the maximum recommended human daily inhalation dose on a mg/ m2basis). 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 of up to 500 mg/ kg/ day (approximately 2500 times the maximum
recommended human daily inhalation dose on a mg/ m2basis) and a 99 week study in hamsters at oral doses of up to 50 mg/ kg/ day (approximately 375 times the maximum recommended
human daily inhalation dose on a mg/ m2basis) 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.
|
|
Ipratropium Bromide
|
| |
Two year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at doses of up to 6 mg/ kg/
day. This dose corresponds to approximately 360 and 180 times the maximum recommended human daily inhalation dose in rats
and mice, respectively, on a mg/ m2basis. 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 of up to 50 mg/
kg/ day (approximately 3000 times the maximum recommended human daily inhalation dose on a mg/ m2basis) was unaffected by ipratropium bromide administration. At doses above 90 mg/ kg/ day (approximately 5400 times the maximum
recommended human daily inhalation dose on a mg/ m2basis), increased resorption and decreased conception rates were observed.
|
Pregnancy, Teratogenic Effects
|
| |
Pregnancy Category C
|
| |
Albuterol
|
| |
Albuterol has been shown to be teratogenic in mice. 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
human daily inhalation dose on a mg/ m2basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/ kg (approximately 10 times the maximum recommended human daily inhalation
dose on a mg/ m2basis). None was observed at 0.025 mg/ kg (approximately one tenth the maximum recommended human daily inhalation dose). 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
1000 times the maximum recommended human daily inhalation dose on a mg/ m2basis).
|
|
Pregnancy Category B
|
| |
Ipratropium Bromide
|
| |
Oral reproduction studies were performed at doses of 10 mg/ kg in mice, 100 mg/ kg in rats and 125 mg/ kg in rabbits. These
doses correspond in each species, respectively, to approximately 300, 600 and 15, 000 times the maximum recommended human
daily inhalation dose on a mg/ m2basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/ kg/ day (approximately
90 and 210 times, respectively, the maximum recommended human daily inhalation dose on a mg/ m2basis). These studies have demonstrated no evidence of teratogenic effects as a result of ipratropium bromide.
|
|
|
Labor and Delivery
|
| |
Because of the potential for beta- agonist interference with uterine contractility, use of albuterol sulfate; ipratropium
bromide 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 albuterol sulfate; ipratropium bromide inhalation aerosol are excreted in human
milk.
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.
|
Ipratropium Bromide
|
| |
Although lipid- insoluble quaternary bases pass into breast milk, it is unlikely that the active component, ipratropium bromide,
would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted
in human milk, caution should be exercised when albuterol sulfate; ipratropium bromide inhalation aerosol is administered
to a nursing mother.
|
|
Pediatric Use
|
| |
Safety and effectiveness of albuterol sulfate; ipratropium bromide inhalation aerosol in pediatric patients have not been
established.
|
|
DRUG INTERACTIONS
|
| |
Albuterol sulfate; ipratropium bromide inhalation aerosol has been used concomitantly with other drugs, including sympathomimetic
bronchodilators, methylxanthines, and steroids commonly used in the treatment of COPD without adverse drug reactions. No formal
drug interaction studies have been performed with albuterol sulfate; ipratropium bromide inhalation aerosol and these or other
medications commonly used in the treatment of COPD.
Anticholinergic Agents
|
| |
Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive
interaction with concomitantly used anticholinergic medications. Caution is therefore advised in the coadministration of albuterol
sulfate; ipratropium bromide inhalation aerosol with other anticholinergic- containing drugs.
|
Beta-Adrenergic Agents
|
| |
Caution is advised in the coadministration of albuterol sulfate; ipratropium bromide inhalation aerosol and other sympathomimetic
agents due to the increased risk of adverse cardiovascular effects.
|
Beta Receptor Blocking Agents
|
| |
These 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 nonpotassium 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 coadministration
of beta agonist- containing drugs, such as albuterol sulfate; ipratropium bromide inhalation aerosol, with nonpotassium sparing
diuretics.
|
Monoamine Oxidase Inhibitors or Tricyclic Antidepressants
|
| |
Albuterol sulfate; ipratropium bromide inhalation aerosol should be administered with extreme caution to patients being treated
with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents because
the action of albuterol on the cardiovascular system may be potentiated.
|
|
ADVERSE REACTIONS
|
| |
Adverse reaction information concerning albuterol sulfate; ipratropium bromide inhalation aerosol is derived from two 12 week,
controlled clinical trials (n=358 for albuterol sulfate; ipratropium bromide inhalation aerosol).
| TABLE 1
All Adverse Events (in Percentages), From Two Large Double- Blind, Parallel, 12 Week Studies of Patients With COPD*
|
| |
|
Albuterol Sulfate; Ipratropium Bromide |
Ipratropium Bromide |
Albuterol Sulfate |
| |
|
206 μg; 36 μg qid |
36 μg qid |
206 μg qid |
| Body as a Whole |
n=358 |
n=362 |
n=347 |
| 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 Disorder (Lower)
|
| |
Bronchitis |
12.3% |
12.4% |
17.9% |
| |
Dyspnea |
4.5% |
3.9% |
4.0% |
| |
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 Disorder (Upper)
|
| |
Upper resp. tract infection |
10.9% |
12.7% |
13.0% |
| |
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 2% or more patients in one or more treatment group in the
12 week, controlled clinical trials.
|
|
Additional adverse reactions, reported in less than 2% of the patients in the albuterol sulfate; ipratropium bromide 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 rash, angioedema of the tongue, lips and face, urticaria (including giant urticaria),
laryngospasm and anaphylactic reaction have been reported, 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 ).
Additional information derived from the published literature and postmarketing surveillance on the use of ipratropium or albuterol
inhalation aerosol, either singly or in combination that is not included in the lists above includes: cases of precipitation
or worsening of narrow- angle glaucoma, acute eye pain, blurred vision, nasal congestion, drying of secretions, mucosal ulcers,
irritation from aerosol, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, heartburn, drowsiness, CNS stimulation,
coordination difficulty, weakness, itching, flushing, alopecia, hypotension, gastrointestinal distress, constipation, and
urinary difficulties.
|
OVERDOSAGE
|
| |
The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute overdosage with ipratropium bromide
is unlikely since it is not well absorbed systemically after aerosol or oral administration. The oral median lethal dose of
ipratropium bromide ranged between 1001 and 2010 mg/ kg in mice (approximately 30, 000 and 60, 000 times the maximum recommended
human daily inhalation dose on a mg/ m2basis, respectively); between 1667 and 4000 mg/ kg in rats (approximately 100, 000 and 240, 000 times the maximum recommended
human daily inhalation dose, respectively, on a mg/ m2basis); and between 400 and 1300 mg/ kg (approximately 80, 000 and 260, 000 times the maximum recommended human daily inhalation
dose, respectively, on a mg/ m2basis) in dogs. Whereas the oral median lethal dose of albuterol sulfate in mice and rats was greater than 2, 000 mg/ kg (approximately
10, 000 and 20, 000 times the maximum recommended human daily inhalation dose, respectively, on a mg/ m2basis), the median lethal inhalational 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), 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 the 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.
|
DOSAGE AND ADMINISTRATION
|
| |
The dose of albuterol sulfate; ipratropium bromide inhalation aerosol is 2 inhalations 4 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 albuterol sulfate; ipratropium bromide 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 albuterol sulfate;
ipratropium bromide 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.
|
HOW SUPPLIED
|
| |
Combivent inhalation aerosol is supplied as a metered- dose inhaler with a white mouthpiece which has a clear, colorless sleeve
and an orange protective cap. The Combivent inhalation aerosol canister should be used with the Combivent inhalation aerosol
actuator only. The actuator should not be used with other aerosol medications. Each actuation meters 120 μg of albuterol sulfate
and 21 μg of ipratropium bromide from the valve and delivers 103 μg of albuterol sulfate (equivalent to 90 μg albuterol base)
and 18 μg of ipratropium bromide from the mouthpiece. Each 14.7 g canister provides sufficient medication for 200 inhalations.
The canister should be discarded after the labeled number of actuations have been used. The amount of medication in each actuation
cannot be assured after this point.
Store between 15- 30°C (59- 86°F). Avoid excessive humidity. For optimal results, the canister should be at room temperature
before use. Shake well before using.
Note
|
| |
The 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. The warning states that
the patient should consult his or her physician if there are any questions about alternatives.
|
|
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| aerosol with adapter - inhalation - 90 mcg- 18 mcg/ inh -
|
| 14.7 gm |
$51.38 |
Combivent
Allscripts Healthcare Solutions
|
54569460000 |
| 14.7 gm |
$65.55 |
Combivent
Boehringer- Ingelheim
|
00597001314 |
| solution - inhalation - 2.5 mg- 0.5 mg/ 3 ml -
|
| 3.0 ml x 30.0 |
$62.40 |
DuoNeb
Dey Laboratories
|
49502067230 |
| 3.0 ml x 60.0 |
$124.80 |
DuoNeb
Dey Laboratories
|
49502067260 |
|
|